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Moniwa, Mariko. "Characterization of the human HDAC1, HDAC2, HDAC3, and chicken erythrocyte histone deacetylase activities." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0018/MQ53197.pdf.
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Silva, Cleandra Gregório. "Avaliação da expressão dos genes HDAC1, HDAC2, HDAC3 e HDAC7 e seus possíveis mecanismos de silenciamento no adenocarcinoma ductal pancreático." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2016. http://hdl.handle.net/10183/143861.
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O adenocarcinoma ductal pancreático (ADP) é uma doença altamente letal e agressiva. Alteração no perfil de acetilação das histonas envolvendo desacetilases de histonas (HDAC), assim como modificações da expressão de miRNAs podem levar ao desenvolvimento tumoral. Neste estudo, foi avaliada a expressão das HDAC1, HDAC2, HDAC3 e HDAC7 em ADP e amostras de tecido pancreático não tumoral (TN) usando análises experimentais e de banco de dados. Os níveis de expressão foram correlacionados com características clínico-patológicas dos pacientes e foi realizada uma investigação in silico de miRNAs reguladores de efeito das HDACs. Os níveis de expressão das HDACs foram avaliadas por qRT-PCR a partir de 25 amostras de ADP e 23 amostras de TN e a análise da expressão diferencial (ED) e correlação entre HDACs e miRNAs em ADP foi realizada utilizando perfis de expressão de seis microarranjos do Gene Expression Omnibus. Potenciais relações miRNA-HDACs foram coletadas em bases de dados de interação de miRNAs. Um valor de P<0,05 foi considerado estatisticamente significativo. Encontramos expressão reduzida em ADP comparado com TN para todas as HDACs analisadas, com P<0,05 para HDAC1, 2 e 3. Entretanto, os fold-changes foram muito baixos e provavelmente sem relevância biológica, e a expressão da HDAC2 e HDAC7 foi correlacionada com a idade ao diagnóstico. Nenhuma outra correlação entre a expressão das HDACs e características clínico-patológicas foi identificada. Análises de ED sugeriram significativa superexpressão das HDAC1, 2 e 7 e subexpressão da HDAC3, contudo todas apresentaram fold-changes pequenos. As análises dos bancos de dados identificaram 728 miRNAs como reguladores das HDACs. Interseções entre os conjuntos de miRNAs (GSE41369 e GSE43796) e aqueles recuperados da análise de expressão diferencial indicaram cinco miRNAs que influenciam a HDAC1 (miR-188-5p, miR-539, miR-708, miR -4269 e miR-3616-3p) e três que influenciam a HDAC2 (miR-4307, miR-944 e miR-195). A expressão das HDACs provavelmente não é um biomarcador de prognóstico robusto para o ADP, uma vez que a expressão diferencial entre os grupos é sutil. Ainda, este e estudos anteriores indicam nenhuma ou pouca associação entre a expressão HDACs e características clínico-patológicas relacionadas com o prognóstico. Finalmente, miRNAs provavelmente não estão exercendo um papel central na regulação da HDACs no ADP.<br>Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and aggressive disease. The disruption of histone acetylation through histones deacetylases (HDACs) and expression regulation by miRNAs can lead to tumor development. In this study we assessed HDAC1, HDAC2, HDAC3 and HDAC7 expression in PDAC and non-tumoral tissue (NT) samples using experimental and databases analysis, correlated their expression levels with clinical and pathological features in patients and performed in silico investigation of HDACs regulation by miRNAs. Expression levels of HDACs were measured by qRT-PCR from 25 PDAC and 23 NT. An analysis of differential expression (DE) and correlation of HDACs and miRNAs in PDAC was performed using six Gene Expression Omnibus microarray datasets. Potential miRNA-HDACs relationships were collected from miRNA interaction databases. A P<0.05 was considered statistically significant. We found reduced expression in PDAC compared with NT for HDAC1, HDAC2 and HDAC3, with P<0.05. Expression levels of HDAC7 did not significantly differ between groups. However, fold-changes were very small and probably not biologically relevant. Only HDAC2 and HDAC7 were associated with age at diagnosis and no other associations between HDAC expression and clinical features were identified. DE analysis suggested significant up-regulation of HDAC1, HDAC2 and HDAC7, and down-regulation of HDAC3, albeit all of them associated with small fold changes. Databases analysis identified 728 miRNAs that could be HDACs regulators. Intersections among the set of miRNAs found in differential expression analysis of GSE41369 and GSE43796 and those retrieved from target prediction identified five miRNAs targeting HDAC1 (miR-188-5p, miR-539, miR-708, miR-4269 and miR-3616-3p) and three targeting HDAC2 (miR-4307, miR-944 and miR-195). HDACs expression is likely not a robust prognostic biomarker in PDAC since differential expression between groups is subtle. Also, this and previous studies indicate no or only very few associations between HDACs expression and clinicopathological features related to prognosis. Finally, miRNAs are probably not exerting a central role in HDAC regulation in PDAC.
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Jamaladdin, Shereen Jamal. "Investigating the physiological role of HDAC1 and HDAC2 in embryonic stem cells." Thesis, University of Leicester, 2016. http://hdl.handle.net/2381/37028.
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Histone deacetylases 1 and 2 (HDAC1/2) are highly similar proteins (83% identical) that form the core catalytic components of corepressor complexes that modulate gene expression. Germline deletion of Hdac1 in mice results in early embryonic lethality and conditional deletion of Hdac1 but not Hdac2 causes precocious differentiation in ES cells. Therefore to further investigate the role of HDAC1/2 during the early embryogenesis, we have generated a compound conditional knockout ES cell line Hdac1ko; Hdac2Het in which HDAC1/2 activity is reduced but not entirley lost. Hdac1ko; Hdac2He cells have a significant reduction in total deacetylase activity and disruption of corepressor complex integrity. The prolifration capicity of Hdac1ko; Hdac2He cells is not inhibited, however, upon differentiation they were predisposed to toward the cardiomyocyte lineage. In most cell types, deletion of both Hdac1 and Hdac2 is required to produce a phenotype, suggesting their activity is redundant. To circumvent this functional redundancy, we generated a double conditional knockout (DKO) cells in which both Hdac1 and Hdac2 can be inactivated simultaneously. Loss of HDAC1/2 results in a 60% reduction in total HDAC activity and a loss of cell viability, which is associated with increased abnormal mitotic spindle, chromatin bridges and miconuclei, suggesting that HDAC1/2 are necessary for accurate chromosome segregation. Transcriptome analysis reveals 1,708 differentially expressed genes in DKO cells including a reduction in the expression of the ES cells core pluripotent factors. HDAC1/2 activity can be regulated in vitro through the binding of inositol tetraphosphate (IP4). By rescuing the viability of DKO cells using wt and mutant forms of HDAC1, we demonstrated that mutations that abolish IP4 binding reduce the activity of HDAC1/2 in vivo. We have also shown that treatment of DKO ES cells with RA results in reduces induction of HOX genes, suggesting a positive role of HDAC1/2 in gene activation as well as gene repression.
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Alexis, Gonneaud. "HDAC1 et HDAC2, des rôles redondants et distincts dans la régulation de l'homéostasie intestinale." Thèse, Université de Sherbrooke, 2017. http://hdl.handle.net/11143/11581.
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Les histones désacétylases HDAC1 et HDAC2 catalysent le retrait d’un groupement acétyle de résidus lysine, dans des protéines histones et non-histones. Les HDAC contrôlent la prolifération, la mort et la différenciation cellulaire. Des propriétés anti-inflammatoires et anti-tumorales ont été attribuées à des inhibiteurs contre les HDAC (HDACi), notamment dans les cellules épithéliales intestinales (CEI). Nous supposons que différents niveaux de HDAC1 ou HDAC2 dans les CEI induisent différentes réponses dans le maintien de l’homéostasie intestinale. Nous avons donc généré des souris hétérozygotes avec un seul allèle de Hdac1 ou Hdac2 dans le contexte de la délétion de l’autre. Les résultats indiquent que les souris Hdac1-/-;Hdac2+/- Villine-Cre présentent un phénotype similaire à celui d’un double mutant, à savoir des défauts d'architecture dans le jéjunum et le côlon, de la dysplasie et hyperplasie, une réduction du nombre de cellules à mucus, mais sans modification du nombre de cellules de Paneth et de la perméabilité épithéliale. Un allèle de Hdac2 n'est donc pas suffisant pour maintenir une homéostasie normale en l'absence de Hdac1. Nous avons aussi vérifié l’effet de la délétion de Hdac1 et Hdac2 à l’âge adulte dans le modèle inductible AhCre. Dans ce contexte, la perte de Hdac1 et Hdac2 entraîne une mortalité accrue après 8 jours, avec un arrêt de prolifération et l’induction de dommages à l’ADN. Nous avons alors exploré l’impact moléculaire de la perte des deux Hdac dans les CEI par une approche protéomique et transcriptomique. Nous avons observé des changements notables dans plusieurs voies de signalisation, associées à la prolifération, à des mécanismes de stress, au métabolisme, surtout lipidique. Ces changements sont en partie régulés post-traductionnellement. Bien que très instructifs, les modèles in vivo ne permettent pas de déterminer si les modifications de l’expression des gènes observées sans Hdac1 et/ou Hdac2 sont intrinsèques aux CEI ou si ces changements dépendent de signaux extrinsèques de la muqueuse ou de la lumière intestinale. Nous avons donc établi des cultures d’entéroïdes à partir de la crypte intestinale, ce qui permet la croissance, l'expansion et la différenciation des CEI progénitrices, sans l’influence de l’environnement. Nous avons entrepris des analyses protéomiques de type SILAC, suite à une inhibition pharmacologique des HDAC de type I, le CI994, ou suite à une délétion génétique de Hdac1 ou Hdac2. L’inhibition pharmacologique entraine un arrêt de prolifération associé à une différenciation altérée en faveur des cellules absorbantes, rappelant le modèle murin sans Hdac1 et Hdac2. Les voies liées à la réplication de l’ADN et au cycle cellulaire sont diminuées. Même si la perte de Hdac1 ou Hdac2 n’affecte pas notablement la croissance et la différenciation des entéroïdes, des voies associées au métabolisme et aux réponses à l’environnement sont augmentées. Au contraire, des entéroïdes sans Hdac1 et Hdac2 ne croissent pas en culture et dégénèrent en moins de 3 jours. Ceci suggère que l’environnement mucosal pourrait soutenir les CEI Hdac1-/-;Hdac2-/- de la niche épithéliale in vivo. Nos données suggèrent que des variations intrinsèques ou extrinsèques de l'activité de HDAC1 et HDAC2 modifient la réponse des CEI à l’environnement et entraînent des perturbations de l'homéostasie intestinale.
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Göder, Anja [Verfasser]. "HDAC1/HDAC2 and PR130 modulate checkpoint kinase-dependent cell fate decisions during replicative stress / Anja Göder." Mainz : Universitätsbibliothek Mainz, 2019. http://d-nb.info/1192034821/34.
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Chrun, Emanuely da Silva. "Expressão imuno-histoquímica das proteínas HDAC1, HDAC2 e HAT1 em queilites actínicas e carcinomas epidermoides de lábio." reponame:Repositório Institucional da UFSC, 2016. https://repositorio.ufsc.br/xmlui/handle/123456789/167471.
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Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências da Saúde, Programa de Pós-Graduação em Odontologia, Florianópolis, 2016.<br>Made available in DSpace on 2016-09-16T14:01:33Z (GMT). No. of bitstreams: 1
339914.pdf: 2025505 bytes, checksum: 8fcd42629046acd83de795d33a29b226 (MD5)
Previous issue date: 2016<br>A acetilação de histonas é uma das alterações epigenéticas que tem sido reconhecida como um processo fundamental com fortes efeitos na regulação da transcrição dos genes. A expressão das enzimas modificadoras de histonas: histonas desacetilases (HDAC) e histona acetiltransferases (HAT), tem sido avaliada em diferentes tipos de tumores malignos. Este trabalho teve como objetivo investigar a expressão de HDAC1, HDAC2 e HAT1, em carcinoma epidermoide de lábio (CEL) e queilite actínica (QA). Para tanto foi realizada uma revisão da literatura e, foram avaliados, através de imuno-histoquímica, 30 casos de CEL e 30 casos de QA além de 28 casos de epitélio não neoplásico (ENN), como controle. Houve diferença estatisticamente significante entre as médias de porcentagem de imunopositividade de HDAC2 entre os grupos de QA (75,07%±29,70) e CEL (51,06%±39,02) (Teste de Kruskal-Wallis, p=0,022). Para HDAC1 as porcentagens de imunomarcação foram de 77,49% (±24,95) no grupo das QA, 74,76% (±25,78) nos CEL e 67,73% (±29,14) no grupo dos ENN (Teste de Kruskal-Wallis, p=0,3625) enquanto para HAT1, as QA mostraram média de imunopositividade de 89,59% (±13,12), os CEL 87,02% (±14,56), e os ENN 84,81% (±19,67) (Teste de Kruskal-Wallis, p=0,7134). Os resultados mostraram maiores níveis de imunopositividade nas QA e nos CEL para HDAC1, HDAC2 e HAT1 em relação ao ENN em grande parte dos casos. A confirmação futura de que estas alterações possam estar envolvidas no desenvolvimento do câncer de lábio, facultará a sua utilização como marcadores de diagnóstico e prognóstico, especialmente das lesões potencialmente malignizáveis, e será imprescindível para evitar ou reduzir procedimentos cirúrgicos por vezes mutiladores por permitir o uso de inibidores de HDAC (HDACi) no tratamento dessas lesões.<br><br>Abstract: Histone acetylation, an epigenetic change, has been recognized as a fundamental process with strong effects on regulation of gene transcription. Expression of histone modifying enzymes: Histone deacetylases (HDACs) and histone acetyltransferases (HAT), has been evaluated in different types of malignant tumors. This study aimed to investigate the expression of HDAC1, HDAC2 and HAT1 in squamous cell carcinoma of the lip (SCCL) and actinic cheilitis (AC). For this, 30 cases of SCCL and 30 cases of AC, as well as 28 cases of non-neoplastic epithelium (NNE), used as a parameter, were evaluated through immunohistochemistry. There was a statistically significant difference between mean percentages of immunopositivity for HDAC2 AC groups (75.07% ± 29.70) and SCCL (51.06% ± 39.02) (Kruskal-Wallis test, p = 0.022). HDAC1 immunostaining percentages were 77.49% (± 24.95) in the AC group, 74.76% (± 25.78) in the CEL, and 67.73% (± 29.14) in the group of NNE. For HAT1, AC showed a mean immunopositivity of 89.59% (± 13.12), SCCL of 87.02% (± 14.56), and NNE of 84.81% (± 19.67). Results showed higher levels of immunopositivity in AC and SCCL to HDAC1, HDAC2 and HAT1 compared to NNE in large part of the cases. Future confirmation that these alterations are involved in the development of lip cancer, would provide their use as diagnostic and prognostic markers, especially precancerous lesions, and is essential for avoiding or reducing surgical procedures, often maiming, for allowing the use of HDAC inhibitors (HDACi) in the treatment of these injuries.
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Hastreiter, Sieglinde Theresia [Verfasser], Günter [Akademischer Betreuer] Schneider, de Angelis Martin [Gutachter] Hrabé, and Günter [Gutachter] Schneider. "Systematic analysis of the class I histone deacetylases HDAC1, HDAC2 and HDAC3 in pancreatic cancer / Sieglinde Theresia Hastreiter ; Gutachter: Martin Hrabé de Angelis, Günter Schneider ; Betreuer: Günter Schneider." München : Universitätsbibliothek der TU München, 2021. http://d-nb.info/123704880X/34.
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Draney, Carrie. "Overexpression of HDAC1 Induces Functional β-cell Mass". BYU ScholarsArchive, 2016. https://scholarsarchive.byu.edu/etd/6573.
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Type 2 diabetes is a metabolic disorder that results in β-cell dysfunction and ultimate destruction, and leads to impaired glucose homeostasis. High rates of proliferation and differentiation of pancreatic β-cells occurs mostly during neonatal development. However, research shows these mechanisms remain intact as β-cell proliferation has been observed during pregnancy and obesity. We have shown that overexpression of the β-cell transcription factor Nkx6.1 is sufficient to induce β-cell proliferation. Exploration of the transcriptional targets of Nkx6.1 has identified histone deacetylase 1 (HDAC1) as a down-stream target of Nkx6.1. Here we demonstrate that HDAC1 overexpression is sufficient to induce β-cell proliferation, enhance β-cell survival upon exposure to apoptotic stimuli and maintains glucose stimulated insulin secretion (GSIS). Our data suggests overexpression of HDAC1 leads to p15/INK4b suppression, a cell cycle inhibitor, potentially explaining the mechanism behind these observed effects. These data demonstrate that HDAC1 overexpression is sufficient to induce β-cell proliferation and enhance cell survival while maintaining glucose stimulated insulin secretion.
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Magri, Laura. "Espressione eterologa e purificazione della istone deacetilasi umana 1 (HDAC1)." Master's thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amslaurea.unibo.it/7605/.
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La proteina umana HDAC1 fa parte della famiglia delle HDAC (Istone Deacetilasi); questi enzimi, ad azione deacetilasica, catalizzano la reazione di rimozione di un gruppo acetile a livello degli istoni, componenti fondamentali della cromatina, la cui struttura influenza il ciclo cellulare e la regolazione dell’espressione genica. L’importanza della proteina in questione, a scopo terapeutico, risiede nello studio degli inibitori ad essa associati, i quali risultano utili a livello farmacologico, come coadiuvanti nelle terapie per la cura di tumori. La produzione di HDAC1 ha previsto l’utilizzo di due diversi ceppi del batterio Escherichia coli, denominati TOP10 e BW25993, che sono serviti come sistemi “ospiti” per l’inserimento del vettore di espressione pBAD-HDAC1 contenente la porzione di DNA che codifica per la proteina ricombinante. Sono state determinate le condizioni più idonee, per entrambi i sistemi analizzati, in modo da massimizzare l’espressione della proteina indotta mediante aggiunta di arabinosio al terreno di coltura. A seconda della combinazione ceppo-vettore, infatti, il livello di espressione ottenuto cambia significativamente. In seguito, gli estratti proteici totali sono stati sottoposti a purificazione mediante diversi passaggi cromatografici ed è stata determinata la resa finale del processo. La caratterizzazione della proteina ricombinante purificata ha evidenziato una forma aggregata, di tipo ottamerico, che potrebbe influenzare l’attività enzimatica. Per questo motivo sono stati portati avanti numerosi tentativi di dissociazione dell’oligomero incubando HDAC1 con diversi agenti. Un effetto disaggregante è stato osservato solo in presenza di due detergenti, SDS (anionico) e CTAB (cationico), i quali hanno permesso di ottenere la proteina in forma monomerica. Tra i due detergenti, l’SDS è risultato più efficace, mentre per il CTAB si richiedono ulteriori indagini ed approfondimenti. Altri studi, infine, sono auspicabili ai fini di migliorare ulteriormente la fase di espressione, in modo da rendere il protocollo di produzione adatto ad un’applicazione a livello industriale.
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Sakamoto, Jiro. "Nardilysin controls intestinal tumorigenesis through HDAC1/p53-dependent transcriptional regulation." Kyoto University, 2019. http://hdl.handle.net/2433/236607.
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Portolano, Nicola. "Investigation of the Sin3a-HDAC1-SDS3 transcriptional co-repressor complex." Thesis, University of Leicester, 2015. http://hdl.handle.net/2381/31993.
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The transcriptional co-repressor Sin3a is a ubiquitous eukaryotic protein complex that has a multitude of critical functions, including the regulation of embryonic development, cell division and maintenance of genomic integrity. It incorporates the highly related HDAC1 and HDAC2 enzymes as its catalytic subunits, which interact with the complex through the HID domain of the Sin3a co-repressor. Sin3a is responsible for deacetylating lysines of Histone tails, condensing chromatin and consequently repressing the transcription of genes. The enzymatic activities of HDAC1 and 2 within Sin3a depend on the association of the Sin3aspecific SDS3 protein, which also interacts with the complex via the HID domain. The mechanism by which Sin3a recruits HDAC1, HDAC2 and SDS3 remains unknown, and elucidating it would represent a big step forward in understanding the epigenetic regulation of genes through the deacetylation of chromatin. The aim of this thesis is to understand how Sin3a recruits its catalytic subunits in to the complex as well as to get a deeper insight into the role of SDS3 in the HID domain by using both structural (X-ray crystallography) and biochemical approaches. Our data suggests that HDAC1 may interact with Sin3a through an extended surface of the co-repressor and that SDS3 stabilizes this interaction by simultaneously binding to HDAC1 and Sin3a. Enzymatic and kinetic assays indicate that Sin3a may be the only Class I HDAC containing complex that is not regulated by IP4. IP4 is a co-factor that regulates the activity of the Class I HDACdependent complexes NuRD and SMRT-NCoR. Thus, our results suggest that Sin3a may have followed a separate evolutionary pattern and its activity may be regulated in a different way.
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Nambiar, Roopa. "Zebrafish hdac1 reciprocally regulates the canonical and non-canonical Wnt pathways." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1150313622.
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Moore-Gagné, Julie. "HDAC1 et la régulation des processus inflammatoires dans les cellules épithéliales intestinales." Mémoire, Université de Sherbrooke, 2012. http://hdl.handle.net/11143/6345.
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Les histones désacétylases (HDACs) contrôlent l'expression des gènes en modifiant la structure de la chromatine par la désacétylation des histones ou en modulant l'activité transcriptionnelle de facteurs de transcription. L'utilisation d'inhibiteurs ciblant les HDACs, les HDACi, a récemment montré un rôle des HDACs dans l'inflammation. Toutefois, comme les HDACi sont non-spécifiques, il est difficile d'identifier les fonctions spécifiques des différents HDACs. Les rôles des HDACs dans l'épithélium intestinal sont peu connus. Les principaux objectifs de ce travail visaient à déterminer les rôles spécifiques de HDAC1 dans les cellules épithéliales intestinales (CEI) et son implication dans la réponse inflammatoire. L'inhibition de l'expression de HDACI dans les CEI de rat, entraîne une augmentation post-transcriptionnelle de HDAC2, une modification de la morphologie cellulaire, une diminution de la prolifération cellulaire, une diminution de l'activité désacétylase associée au complexe corépresseur Sin3 et une modification de la réponse au HDACi trichostatin A (TSA). De plus, en réponse à l'IL-1[beta], la perte de HDACI diminue l'expression protéique des facteurs de transcription NF-?B et C/EBP[beta] tout en entraînant une prolongation de leur phosphorylation. L'absence de HDAC1 diminue également la phosphorylation et l'expression des MAPKs p38 et JNK, de base ou en réponse à l'IL-1[beta]. Ensuite, l'expression de gènes de réponse inflammatoire en réponse à l'IL-1[beta] a été analysée. Suivant la perte de HDACI, cinq patrons d'expression ont ainsi été obtenus : 1) augmentation des niveaux de base et induits (Hp, Kng 1), 2) réduction des niveaux de base et niveaux induits normaux (Cc12, Cc15, Cc120, Cxcll, C3, iNOS), 3) augmentation des niveaux induits (Cxcl2), 4) réduction des niveaux de base et induits (A2m) et 5) aucune modulation (Lcn2, GAPDH). La sécrétion de cytokines est également perturbée en l'absence de HDAC I : 1) diminution des niveaux de base et augmentation des niveaux induits (Cc12, Cxcl3), 2) diminution des niveaux induits (Cc120, Cxcl5, Cx3c11) et 3) augmentation des niveaux induits (Cxcl2, Timpl). HDACI est aussi impliquée dans le contrôle de la réponse au stress du réticulum endoplasmique puisqu'un délai dans l'induction de la protéine CHOP est observé dans les cellules n'exprimant pas HDACI, en réponse à la tunicamycine. Nos résultats démontrent que HDACI est un régulateur majeur de l'homéostasie épithéliale intestinale, incluant la réponse inflammatoire et le stress du réticulum endoplasmique, et que HDAC1 peut agir autant comme coactivateur ou corépresseur transcriptionnel.
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Ignatius, Myron Steve. "Zebrafish Hdac1 Is Reiteratively And Differentially Required During Neural Crest Cell Development And Hdac1 Is A Positive Regulator Of The Non Canonical Wnt Signaling Pathway." Columbus, Ohio : Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1211981873.
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Unal, Eroglu Arife. "REGULATION OF NEURAL CREST DEVELOPMENT REQUIRES FUNCTIONAL INTERACTIONS BETWEEN HDAC1, TFAP2A AND FOXD3." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1357141637.
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Gonneaud, Alexis. "L’histone désacétylase HDAC1 influence la réponse à des stress métaboliques dans les cellules épithéliales intestinales." Mémoire, Université de Sherbrooke, 2014. http://hdl.handle.net/11143/5459.
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Introduction : Les histones désacétylases (HDAC) catalysent le retrait d’un groupement acétyl de résidus lysine. Leurs substrats comprennent les histones et des facteurs de transcription comme NF-κB p65 ou des kinases comme AMPK. Les HDACs contrôlent la prolifération, la mort et la différenciation cellulaires. Des propriétés anti-inflammatoires et anti-tumorales ont été attribuées à des inhibiteurs contre les HDAC, notamment dans les cellules épithéliales intestinales (CEI). Nous avons montré que la perte de HDAC1 entraîne une diminution de la croissance et cela, sans augmentation significative des inhibiteurs du cycle cellulaire comme p21 ou p27 (Moore-Gagné, 2012). J’ai alors hypothétisé que l’absence de HDAC1 pouvait mener à des défauts dans les voies de synthèse ou de production d’énergie. Je me suis donc intéressé à l’étude des voies métaboliques qui participent notamment à la production d’acétyl-CoA, le principal donneur de groupement acétyl, groupement nécessaire pour l’acétylation des histones. Des études récentes ont démontré que les voies métaboliques, en modulant les niveaux d’acétyl-CoA, altèrent les patrons d’acétylation. J’ai donc voulu déterminer le rôle de HDAC1 dans la transmission de stress métaboliques dans les CEI. Méthodes : L’expression de HDAC1 a été réduite dans les cellules de cryptes intestinales de rat (IEC-6) par infection lentivirale de shARN contre HDAC1. Les cellules ont été cultivées avec ou sans glucose et sérum, avec plusieurs métabolites du cycle de Krebs, dont l’acétate, le citrate, le fumarate ou avec le peroxyde d’hydrogène pour induire un stress oxydant. L’acétylation des histones H3 et H4 ont été déterminées par immunobuvardage avec des anticorps contre des histones acétylées. La viabilité cellulaire a été mesurée par essai MTT, et les radicaux libres par oxydation du DCFDA. Les protéines différemment exprimées ont été identifiées par incorporation d’isotopes plus lourds d’acides aminés, suivi de spectrométrie de masse (SILAC) et analysé informatiquement (logiciel MaxQuant). Les cibles repérées ont été analysées par RT-PCR semi-quantitatif et par immunobuvardage. Les niveaux de régulateurs métaboliques tels que l’AMPK ou l’acétyl-CoA carboxylase (ACC) ont été déterminés par immunobuvardage. Le nombre de mitochondries a été observé par fluorescence. Résultats : La perte de HDAC1 augmente globalement l’acétylation des histones. L’absence de glucose et de sérum diminue les niveaux d’acétylation des histones. L’absence de HDAC1 augmente la viabilité cellulaire en présence de fumarate et citrate, et en absence de glucose et sérum. Les cellules shHDAC1 montrent une viabilité accrue après un traitement au peroxyde d’hydrogène. Ceci corrèle avec des niveaux de base diminués de radicaux libres et une surexpression de Sod2, une protéine anti-oxydante. Les résultats ont montré que la perte de HDAC1 comme l’addition de certains métabolites modifient le patron d’acétylation cellulaire, suggérant des perturbations dans les niveaux d’acétyl-CoA. L’analyse SILAC a mis en évidence une altération des voies de signalisation liées à différents processus métaboliques, comme la phosphorylation oxydative et la synthèse des protéines. L’activation constante de l’AMPK suggère que les cellules shHDAC1 sont en restriction calorique permanente, ce qui les rend moins sensibles au stress oxydant et métabolique par rapport aux cellules shCtrl. Les cellules shHDAC1 présentent une augmentation de la quantité de mitochondries, suggérant un défaut de génération d’ATP. Un shunt d’acétyl-CoA vers le noyau serait envisageable. Conclusion : En modifiant les voies métaboliques liées à la production d’acétyl-CoA, la perte de HDAC1 protège les CEI des réactions de stress. HDAC1 contrôle la réponse des CEI à des stress métaboliques.
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Salem, Abdou Houssein. "Understanding C/EBPbeta LAP/LIP Transcriptional and Adipogenic Potential Through Regulation by HDAC1 and GCN5." Thèse, Université d'Ottawa / University of Ottawa, 2011. http://hdl.handle.net/10393/19998.
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The CCAAT/Enhancer Binding Protein Beta (C/EBPβ) is part of the leucine zipper family of transcription factors and is involved in a myriad of processes including cellular proliferation and differentiation. C/EBPβ is expressed as three isoforms (LAP*, LAP, LIP), translated from a single mRNA by a leaky ribosomal scanning mechanism. While LAP* and LAP have activating functions, LIP is recognized as being a repressor of transcription due to its lack of activation domains.
Numerous studies have shown that C/EBPβ acetylation state modulates its activity in a promoter-specific manner. For instance, the acetyltransferases GCN5/PCAF and the deacetylase complex mSin3A/HDAC1 regulate C/EBPβ activity on the C/EBPa promoter. GCN5/PCAF-mediated acetylation of C/EBPβ was shown to positively affect its transcriptional activity in a steroid-dependent mechanism via the glucocorticoid receptor (GR). GR relieves HDAC1 association from C/EBPβ by targeting the deacetylase for proteasomal degradation, hence favouring GCN5-mediated acetylation of C/EBPβ and allowing maximum activation capacity to be reached. In order to further elucidate C/EBPβ activation, I sought to characterize the interplay between GCN5 and HDAC1 in regulating C/EBPβ LAP/LIP activity during murine adipogenesis by identifying their binding domain in C/EBPβ.
I identified a minimal domain located within regulatory domain 1 (RD1) of C/EBPβ that is required for both GCN5 and HDAC1 binding. Furthermore, the loss of the identified domain in C/EBPβ appears to partially mimic the GR effect, thus giving C/EBPβ a higher basal transcriptional activity that accelerates NIH 3T3 and 3T3 L1 adipogenesis. Moreover, I also showed that the LIP isoform inhibitory mode of action is partially mediated through the mSin3A/HDAC1 repressor complex, which gives LIP an active repressor function. In addition to LIP inhibitory function, I also showed that a cysteine residue located in LAP* negatively regulates its transactivating function during murine adipogenesis.
Although RD1 of C/EBPβ has been suggested to act as a negative regulatory domain, I showed that only five residues are responsible for most of its inhibitory effect. Hence, in an attempt to further define sub-domains within RD1, I characterized a new positive regulatory domain at its N-terminal region, which seems to be required for C/EBPβ activity in a promoter-specific manner.
In conclusion, this study not only supports previously hypothesized mechanisms by which C/EBPβ is regulated, but it also redefines the contribution of LAP*, LAP and LIP in regulating transcription. Most importantly, the results emphasize the countless possibilities by which C/EBPβ transactivation potential could be modulated during cellular differentiation.
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Kuzmochka, Claire. "Investigating the role and regulation of histone deacetylase 1 (HDAC1) in glucocorticoid-potentiated preadipocyte differentiation." Thesis, University of Ottawa (Canada), 2010. http://hdl.handle.net/10393/28688.
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Corticosteroids promote central obesity in humans and enhance the efficiency of preadipocyte differentiation in culture. The glucocorticoid receptor(GR) stimulates preadipocyte differentiation, in part, by enhancing transcription of the adipogenic commitment factor C/EBPalpha. GR is hypothesized to enhance C/ebpalpha transcription through a mechanism that involves promoting the titration, and subsequent degradation, of the co-repressor histone deacetylase 1(HDAC1) from the C/EBPalpha promoter.
The first section of this investigation demonstrates that HDAC1, and not HDAC2 is involved in suppressing GR-potentiated preadipocyte differentiation and that the ability of HDAC1 to inhibit the adipogenic program is dependent on its deacetylase activity. Furthermore, the results imply that additional inhibitors assist HDAC1 in actively suppressing C/ebpalpha transcription in the absence of corticosteroids, as well as indicating that HDAC1 likely has supplementary deacetylation targets at the C/EBPalpha promoter, in addition to K98,101 and 102 of C/EBPbeta. Finally, we demonstrate that D181A HDAC1 is a catalytically compromised, dominant negative mutant of HDAC1.
In the second section of this investigation we provide evidence that, contrary to published results, acetylation of HDAC1 at lysine residues 218, 220, 432, 438, 439 and 441 does not inactivate the deacetylase activity of the enzyme. However, we propose a new hypothesis which reconciles our results with the published findings: Alterations in the acetylation status of the six identified lysine residues of HDAC1 regulate the substrate specificity of the enzyme, rather than its catalytic activity.
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Adhikari, Sandeep. "FUNCTIONAL CHARACTERIZATION OF IDENTIFIED DEAF1 VARIANTS AND SIGNIFICANCE OF HDAC1 INTERACTIONS ON DEAF1-MEDIATED TRANSCRIPTIONAL REPRESSION." OpenSIUC, 2021. https://opensiuc.lib.siu.edu/theses/2838.
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Deformed epidermal autoregulatory factor 1 (DEAF1) encodes a transcription factor essential in early embryonic and neuronal development. In humans, mutations in the DNA binding domain of DEAF1 cause intellectual disability together with clinical characteristics collectively termed DEAF1-associated neurodevelopmental disorders (DAND). The objective of this study is to 1) assess the pathogenicity of newly identified variants using established functional assays, and 2) confirm and map the interaction domain of DEAF1 with HDAC1 and evaluate the importance of DEAF1-HDAC1 interaction on DEAF1-mediated transcriptional repression. Exome sequencing analysis identified six de novo DEAF1 mutations (p.D200Y, p.S201R, p.K250E, p.D251N, p.K253E, and p.F297S). Promoter activity experiments indicate DEAF1 transcriptional repression activity was altered by p.K250E, p.K253E, and p.F297S. Transcriptional activation activity was altered by p.K250E, p.K253E, p.F297S, and p.D251N. Combined with clinical phenotype of the patients, this work establishes the pathogenicity of new DEAF1 variants. Previous studies identified a potential protein interaction between DEAF1 and several proteins of the nucleosome remodeling and deacetylating (NuRD) complex including Histone Deacetylase 1 (HDAC1), Retinoblastoma Binding Protein 4 (RBBP4), Methyl CpG Binding Domain Protein 3 (MBD3). GST pull-down and co-immunoprecipitation (CoIP) assays confirmed and mapped the interaction with HDAC1 between amino acids 113 – 176 of DEAF1. To determine whether DEAF1-mediated repression requires HDAC1 activity, HEK293t wild type or CRISPR/Cas9-mediated DEAF1 knockout cells were treated with the HDAC inhibitor Trichostatin A (TSA). Interestingly, this study demonstrates that the requirement of HDAC1 activity on DEAF1-mediated transcriptional repression activity is target gene specific and expands our understanding of DEAF1 mediated transcriptional repression.
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Chandru, Aditya. "A tale of two epigenetic protein pairs : characterizing the Sin3aTET1 complex and the decrotonylation activity of HDAC1/2." Thesis, University of Leicester, 2018. http://hdl.handle.net/2381/42853.
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Characterizing the Sin3a-TET1 Complex: TET 1 permits active DNA demethylation, promoting a transcriptionally permissible environment by preventing aberrant methylation. Contrastingly, Sin3a is the scaffold-protein central to the eponymous co-repressor complex. Histone deacetylases 1 and 2 (HDACl/2) form the enzymatic core of this protein-multiplex where they function to increase DNA:histone cohesion, thereby repressing gene expression. Despite these divergent activities, TET1 was found to bind Sin3a and recruit it to target genes. Mapping this interaction was integral to characterizing the TET1:Sin3a complex. An evolutionarily conserved 892-VAIEALTQLS-901 region in TET1 was identified. This a-helix was confirmed to bind to Sin3a's PAH1 domain. Complex formation was found to be equimolar and NMR illustrated the association to the resolution of individual residues. The TET1 Sin3a interaction domain (SID)'s bulky hydrophobic residues, and smaller adjacent alanines, bound to 18 PAH1 amino acids in a manner that resembles a key fitting a lock. The SAP25-SID interacts with these same PAH1 residues and binds in an identical orientation to TETI. While it initially seems curious that Sin3a and TET1 should bind, TETI operates as a net transcriptional repressor in cells. This activity appears independent of TET1's enzymatic function and instead likely relies on HDAC recruitment through the Sin3a co-repressor complex. This was confirmed in a reporter assay where Gal4 TET1-SID fusions repressed gene expression in a manner that was proportional to the fusion's ability to bind Sin3a. Characterizing the Decrotonylation Activity of HDAC1/2: In addition to Lys-Acetylation, a constellation of different Lys-Acylations have recently been discovered, including crotonylation. The ubiquity and nuclear localization of HDAC1/2 suggested their involvement in decrotonylation. HDAC1/2 DKO ESCs confirmed HDAC1/2's absence led to hypercrotonylation of the core histones. A novel decrotonylase assay established HDAC1/2 as potent lysine decrotonylases and that this activity could be recruited to lysine residues, by LSD1, via the CoREST complex.
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Liu, Chia Yi. "Tyrosine Phosphorylation of p68 RNA Helicase Promotes Metastasis in Colon Cancer Progression." Digital Archive @ GSU, 2012. http://digitalarchive.gsu.edu/biology_diss/117.
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The initiation of cancer metastasis usually requires Epithelial-Mesenchymal Transition (EMT), by which tumor cells lose cell-cell interactions and gain the ability of migration and invasion. Previous study demonstrated that p68 RNA helicase, a prototypical member of the DEAD-box RNA helicases, functions as a mediator to promote platelet-derived growth factor (PDGF)-induced EMT through facilitating nuclear translocation of β-catenin in colon cancer cells. In this context, p68 RNA helicase was found to be phosphorylated at the tyrosine 593 residue (referred as phosphor-p68) by c-Abl kinase, and this phosphorylation is required for the activation of β-catenin signaling and the consequent EMT. The phosphor-p68 RNA helicase-mediated EMT was characterized by the repression of an epithelial marker, E-cadherin, and the upregulation of a mesenchymal marker, Vimentin. E-cadherin, a major cell-cell adhesion molecule that is involved in the formation of adherens junctions, has been shown to sequester β-catenin at the cell membrane and thus inhibit its transcriptional activity. The functional loss of E-cadherin is the fundamental event of EMT. Despite the role of phosphor-p68 RNA helicase in regulating nuclear translocation of β-catenin, whether phosphor-p68 is involved in the regulation of E-cadherin remains unknown. Here, our data indicated that phosphor-p68 RNA helicase initiated EMT by transcriptional upregulation of Snail1, a master transcriptional repressor of E-cadherin. The data suggest that phosphor-p68 RNA helicase displaced HDAC1 from the chromatin remodeling MBD3:Mi-2/NuRD complex at the Snail1 promoter, thereby activating the transcription of Snail1. In the xenograft tumor model, abolishing the phosphorylation of p68 RNA helicase by the expression of Y593F mutant resulted in a significant reduction of metastatic potential in human colon cancer cells. Analyses in the colon cancer tissues also revealed that the tyrosine 593 phosphorylation level of p68 RNA helicase is substantially enhanced in the tumor tissues comparing to that in the corresponding normal counterparts, suggesting a correlation of phosphor-p68 and tumor progression. In conclusion, we showed that tyrosine phosphorylation of p68 RNA helicase positively correlated to the malignant status of colon cancer progression. The molecular basis behind this correlation could be partly through the transcriptional regulation of Snail1.
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Eser, Stefan [Verfasser], Dieter K. M. [Akademischer Betreuer] Saur, Jörg H. [Akademischer Betreuer] Kleeff, and Roland M. [Akademischer Betreuer] Schmid. "Ein SNAIL/HDAC1/HDAC2 Repressorkomplex reprimiert die E-cadherin Expression und reguliert die Metastasierung des duktalen Pankreaskarzinoms in vivo / Stefan Eser. Gutachter: Jörg H. Kleeff ; Roland M. Schmid ; Dieter K. M. Saur. Betreuer: Dieter K. M. Saur." München : Universitätsbibliothek der TU München, 2015. http://d-nb.info/1070372358/34.
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Ferreira, Roger. "Etude du rôle de l'histone désacetylase HDAC1 dans le mécanisme de répression du facteur E2F par les protéines à poche, au cours du cycle cellulaire." Paris 11, 2001. http://www.theses.fr/2001PA11T052.
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Le facteur de transcription E2F joue un rôle crucial dans le contrôle du cycle cellulaire. Il active la transcription de nombreux gènes impliqués dans la progression des cellules vers la phase de synthèse de l'ADN, la phase S. Dans les cellules en quiescence et au cours de la phase G1 du cycle cellulaire, le facteur E2F est régulé négativement par les membres d'une famille de protéines, les protéines à «poche » dont la protéine Rb est le prototype. Le maintien de cette régulation dépendante du cycle cellulaire semble être primordial au bon déroulement de la division cellulaire. En effet la protéine Rb est une cible majeure des protéines virales transformantes et est mutée dans un grand nombre de tumeurs humaines. L'un des mécanismes par lesquels Rb réprime la transcription semble impliquer le recrutement de la protéine HDAC1 sur les promoteurs de gènes cibles de E2F. La protéine HDAC1 fait partie d'une famille d'enzymes, les «histones désacétylases », famille de protéines qui participe à la régulation transcriptionnelle en modifiant la structure chromatinienne. Dans l'étude présentée ici, nous avons, dans un premier temps, analysé le rôle de la protéine HDAC1 dans la répression transcriptionnelle par les deux autres protéines à poche, les protéines p107 et p130, et dans un deuxième temps, étudié le recrutement, de manière dépendante du cycle cellulaire, de la protéine HDAC1 sur le promoteur d'un gène cible du complexe « protéine à poche/E2F ». Nous avons montré que, comme la protéine Rb, les protéines p107 et p130 interagissent avec l'histone désacétylase HDAC1 et que la répression transcriptionnelle par ces protéines est, en partie, conséquente à cette interaction. Afin de montrer le recrutement effectif de la protéine HDAC1 sur le promoteur du gène DHFR, gène régulé par E2F, nous avons utilisé la technique d' «lmmunoPrécipitation de la Chromatine (ChiP)». Nous avons montré que la protéine HDAC1 est présente sur ce promoteur au cours de la phase G1 du cycle cellulaire et qu'elle est relarguée lorsque les cellules progressent vers la phase S. Ce relargage de la protéine HDAC1 du promoteur DHFR est accompagné d'une hyperacétylation des lysines 5 et 12 de l'histone H4 au niveau de ce promoteur, et de l’activation transcriptionnelle du gène DHFR<br>The transcription factor E2F plays a key role in the control of the cell cycle. It activates the transcription of many genes involved in cell cycle progression towards S phase, the phase of DNA synthesis. In quiescent cells and during the G1 phase of the cell cycle, the E2F factor is negatively regulated by members of the so called « pocket protein » family, of which Rb is the prototype. The maintenance of this cell-cycle dependant regulation seems to be crucial for the regulation of cell division. Actually, Rb protein is a major target of transforming viral proteins and is mutated in many human tumors. One of the mechanisms by which Rb represses transcription seems to involve the recruitment of HDACl protein on E2F-target genes promoters. HDACl belongs to a family of enzymes, the Histone Deacetylases, that participate in transcriptional regulation by modifying the chromatin structure. In this present study, we have analyzed the role of HDACl in the transcriptional repression of pocket proteins and its cell-cycle dependant recruitment to promoters of E2F target genes. We have shown that, like for Rb, the p107 and p130 proteins interact with histone deacetylase HDACl and that they accomplish transcriptional repression partly, due to this interaction. In order to show effective recruitment of HDACl on the DHFR promoter, we have used Chromatin ImmunoPrecipitation (ChiP). We have shawn that the HDACl protein is present on the DHFR promoter during the G1 phase of the cell cycle and that it is released when cells progress towards S phase. This release of HDACl protein from the DHFR promoter is followed by hyperacetylation of histone H4 on lysines 5 and 12, on this same promoter, and by transcriptional activation of DHFR gene
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Lu, Ping. "Identification of Gon4-like as a factor that is essential for B lymphopoiesis and capable of mediating transcriptional repression." Diss., University of Iowa, 2010. https://ir.uiowa.edu/etd/849.
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The B cell population is one of the key components of the adaptive immune system, which protects the host from a tremendous variety of pathogens by producing antibodies. B cells develop from hematopoietic stem cells through a pathway known as B lymphopoiesis. This is a process accompanied by intensive gene expression reprogramming. By the end, genes appropriate for the B lineage are activated and those that are not are continuously repressed. The regulation of lineage gene expression is conferred by a network of transcriptional regulators. Although some key components have been defined, more factors, especially those orchestrating the repression of non-B lineage genes, remain to be identified.
Chemically induced mutagenesis is a potent way of identifying genes with critical biological functions. Injection of n-ethyl-n-nitrosourea, a mutagen, has generated a unique point mutation in the mouse Gon4-like (Gon4l) gene that specifically causes a loss of peripheral B cells while maintaining the T cell population. The mutation is therefore named Justy for Just T cells. The goal of this thesis project is to analyze the Justy mice and provide insights into the mechanisms underlying the regulation of B lymphopoiesis.
The work presented here demonstrates that the protein encoded by Gon4l is essential for early B lymphopoiesis, which is likely through the repression of non-B lineage genes. Gon4l protein contains conserved domains implicated in transcriptional repression and associates in a complex with the transcriptional repression mediators Yin Yang 1 and Sin3a/HDAC1, after these proteins are transiently expressed in cell lines. When bound to DNA, Gon4l is capable of repressing a nearby promoter and this function correlates with its ability to form a complex. Therefore, these results suggest that Gon4l may function as a transcriptional regulator by employing its associated co-factors in the identified complex. Lastly, a wide spectrum of tumors developed in Justy mice, indicating that Gon4l can also act as a tumor suppressor.
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Meunier, Elise. "Interrelations entre les protéines Rho et le récepteur des oestrogènes alpha dans des modèles de cancers mammaires." Toulouse 3, 2010. http://thesesups.ups-tlse.fr/1000/.
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L'hormonothérapie est recommandée dans environ deux tiers des cancers du sein exprimant le récepteur des œstrogènes (RE) et/ ou le récepteur de la progestérone (RP). Cependant, il y a apparition systématique de résistances qui imposent la recherche de nouvelles cibles thérapeutiques. Les œstrogènes agissent via le REa mais il a été démontré des interrelations majeures entre le REa et la voie de facteurs de croissance en particulier avec les protéines Rho. L'objectif de ce travail de thèse était de déterminer s'il existe un dialogue entre le REa et les protéines Rho A, B et C, les éventuels mécanismes mis en jeu et l'implication dans la tumorigenèse mammaire. Dans un premier temps, nos résultats ont permis de mettre en évidence que RhoB est un élément clé de la régulation de l'expression du REa et du RP. Pour cela, nous avons utilisé des modèles cellulaires, animaux et des tumeurs de patientes. Dans un second volet de ce travail, nous nous sommes concentrés sur les effets de RhoA et RhoC sur les activités du REa. RhoA et RhoC modifient également le recrutement de REa sur les promoteurs de différents gènes cibles du REa mais sans corrélation avec les modulations d'activités transcriptionnelles observées. A l'inverse de RhoB, RhoA diminue l'expression du REa alors que RhoC n'a pas d'effet. L'ensemble de ces résultats nous a donc permis de montrer que malgré leur très forte homologie, RhoA,B et C ont toutes 3 des rôles, mais différents, sur l'expression et les effets transcriptionnels du REa dans les cellules de cancers du sein. De plus, l'importance de RhoB comme agent pro-prolifératif dans des cellules mammaires hormonodépendantes est un axe majeur à développer<br>Hormone therapy is recommended in approximately two thirds of breast cancers which express the Estrogen Receptor alpha (ERa) and/or Progesterone Receptor (PR). Nevertheless, there are many cases of systemic resistance to the treatment that impose to find new therapeutic targets. Estrogens act via ERa but cross-talks between ERa and growth factor pathways have been demonstrated, especially with Rho proteins. The aim of this study was to determine the cross-talks existing between ERa and the RhoA, B and C proteins, the mechanisms of these cross-talks and their involvement in mammary tumorigenesis. First of all, our results showed that RhoB controls ERa and PR expressions. For this, we used mammary cell lines, RhoB deficient mice and tumors from patients. A positive regulation loop has been demonstrated between RhoB and ERa. RhoB appears then to be pro-oncogenic in hormone-dependant mammary tumors cells, inversely to its usual role of tumor suppressor gene for other cancer locations. Moreover our results clearly show that RhoB controls ERa transcriptional activities and the recruitment of its cofactors (including ERa itself) on PR promotor. In a second part, we analyzed the effects of RhoA and RhoC on ERa activities. RhoA and RhoC modify too ERa recruitment on 4 of its target genes, but without any correlation with the observed modulations of transcription. Opposite to RhoB, RhoA decreases ERa expression whereas RhoC has no effect. In a third part, we identified another reciprocal positive regulation between RhoB and HDAC1. The first results obtained in vitro have been confirmed in RhoB deficient mice. Taken together, these results suggest that in spite of their sequence homology, RhoA, B and C all act, but in different manners, on ERa expression and transcriptional activities in mammary cancer cells. Furthermore, the importance of RhoB as proliferative agent in mammary hormone dependant cancer cells is a major research area to consider
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Lin, Chunru. "Functional Role of Dead-Box P68 RNA Helicase in Gene Expression." Digital Archive @ GSU, 2006. http://digitalarchive.gsu.edu/biology_diss/10.
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How tumor cells migrate and metastasize from primary sites requires four major steps: invasion, intravasation, extravasation and proliferation from micrometastases to malignant tumor. The initiation of tumor cell invasion requires Epithelial-Mesenchymal Transition (EMT), by which tumor cells lose cell-cell interactions and gain the ability of migration. The gene expression profile during the EMT process has been extensively investigated to study the initiation of EMT. In our studies, we indicated that tyrosine phosphorylation of human p68 RNA helicase positively associated with the malignant status of tumor tissue or cells. Studying of this relationship revealed that p68 RNA helicase played a critical role in EMT progression by repression of E-cadherin as an epithelial marker and upregulation of Vimentin as a mesenchymal marker. Insight into the mechanism of how p68 RNA helicase represses E-cadherin expression indicated that p68 RNA helicase initiated EMT by transcriptional upregulation of Snail. Human p68 RNA helicase has been documented as an RNA-dependent ATPase. The protein is an essential factor in the pre-mRNA splicing procedure. Some examples show that p68 RNA helicase functions as a transcriptional coactivator in ATPase dependent or independent manner. Here we indicated that p68 RNA helicase unwound protein complexes to modulate protein-protein interactions by using protein-dependent ATPase activity. The phosphorylated p68 RNA helicase displaced HDAC1 from the chromatin remodeling MBD3:Mi2/NuRD complex at the Snail promoter. Thus, our data demonstrated an example of protein-dependent ATPase which modulates protein-protein interactions within the chromatin remodeling machine.
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New, Maria. "Role of HR23B, HDAC6 and Myd88 and their interplay in response to HDAC inhibitor treatment." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:096a4afc-98fa-41d5-b163-9287984cb1fa.
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Abnormal epigenetic control is a common early event in tumour progression, and aberrant acetylation in particular has been implicated in tumourigenesis. Histone deacetylases (HDACs) are enzymes that regulate acetylation of chromatin and a variety of other non-histone substrates. Significantly, HDAC inhibitors are potent anti-proliferative agents and exhibit clinical activity in lymphoproliferative and haematological maligancy. However, the mechanistic details by which HDAC inhibitors affect proliferation remain to be elucidated. I have explored the cellular processes affected by HDAC inhibitors, and begun to illuminate a new pathway, regulated by HDAC, which impinges on the cellular effect of HDAC inhibitors. My results suggest that the proteins HR23B and Myd88 are important sensitivity determinants for HDAC inhibitor treatment, and that their interplay with HDAC6 dictates cell fate choice between survival by autophagy or apoptosis.
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Castaneda, Adrian Lance. "Selective histone deacetlyase inhibition decreases disease in lupus-prone mice." Thesis, Virginia Tech, 2016. http://hdl.handle.net/10919/72952.
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Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme that acetylates several proteins that are involved in the immune response. HDAC6 inhibition has been shown in various models to decrease inflammation by altering various proteins involved in the dysregulation of B and T cell responses. In our current studies we sought to determine if HDAC6 inhibition would decrease disease in lupus-prone mice using two murine mouse models of SLE: MRL/lpr mice and NZB/W F1 mice. Both mouse models were fed a rodent diet formulated with the selective HDAC6 inhibitor ACY-738 (N-hydroxy-2-(1-phenylcycloproylamino) pyrimidine-5-carboxamide). NZBW mice received 18 weeks of treatment starting at 16-weeks-of-age and had an average of 57.3 +/- 14.6 ng/mL of ACY-738 in the plasma. MRL/lpr mice received 7 weeks of treatment starting at 11-weeks-of-age and had an average of 78.5 +/- 17.3 ng/mL of ACY-738 in the plasma. Controls received either dexamethasone 5x a week or were left untreated. As the mice aged, body weight, urine protein, and blood sera was collected weekly. Spleen cells were isolated following euthanasia for flow cytometry and kidneys were also collected for histological analyses. We found that in both mouse models that mice treated with ACY-738 had reduced splenic weight and IgG immunoglobulin isotypes. MRL/lpr mice that were treated with ACY-738 had a reduction in the number of IL-17+, ROR-gamma-t TH17 cells. NZBW/ F1 mice that received ACY-738 treatment also had a reduction in the TH17 cells and we observed a significant reduction in kidney pathology. Selective HDAC6 targeting may warrant future investigations as a potential therapeutic target for the treatment of SLE.<br>Master of Science
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Gries, Alexandre. "Etude des Histones Désacétylases (HDACs) comme cibles thérapeutiques dans le cancer gastrique." Thesis, Strasbourg, 2018. http://www.theses.fr/2018STRAJ045.
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En raison de l’efficience des traitements, le taux de survie globale à 5 ans des patients avec un cancer gastrique (CG) est d’environ 15%. A l’heure actuelle, il n’existe pas de stratifications des patients permettant de prescrire un protocole de traitements efficace. Durant ma thèse, j’ai établi le rôle de HDAC4 dans la sensibilité des cellules de CG au Cisplatine. J’ai montré que cette réponse semble dépendre du type de CG (intestinal ou diffus) et du statut p53 des cellules cancéreuses. J’ai souligné l’intérêt de combiner un inhibiteur des HDACs (SAHA) avec les chimiothérapies à base de dérivés de platine (PDC : Cisplatine, Oxaliplatine) afin de promouvoir leurs effets cytotoxiques. De manière intéressante, j’ai observé que la réponse aux traitements combinés est différente suivant le statut p53 des cellules cancéreuses. Ces résultats permettent d’ouvrir de nouvelles perspectives dans l’utilisation des traitements combinés PDC + SAHA dans la thérapie du CG. En particulier, le facteur p53 qui est souvent muté dans les CG, pourrait être un marqueur thérapeutique pour un tel protocole de traitement<br>Due to the efficiency of treatments, the 5-year overall survival rate for patients with gastric cancer (GC) is approximately 15%. Currently, there is no stratification of patients to prescribe an effective treatment protocol.During my thesis, I established the role of HDAC4 in the sensitivity of GC cells to Cisplatin. I have shown that this response seems to depend on the type of GC (intestinal or diffuse) and the p53 status of cancer cells. I emphasized the interest of combining an HDAC inhibitor (SAHA) with platinum derivative chemotherapies (PDC: Cisplatin, Oxaliplatin) to promote their cytotoxic effects. Interestingly, I observed that the response to combination treatments is different depending on the p53 status of the cancer cells.These results open new perspectives in the use of PDC + SAHA combination therapies in GC. The p53 factor that is often mutated in GC could be a therapeutic marker for a such treatment protocol
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Calvo, Vidal Verónica Alejandra. "Searching for a functional relationship between the breast cancer susceptibility gene BRCA1 and the progesterone receptor in breast cancer cells." Doctoral thesis, Universitat Pompeu Fabra, 2009. http://hdl.handle.net/10803/7239.
Full textAbstract:
Germ-line mutations in the breast cancer susceptibility gene BRCA1 strongly increase the risk of developing breast and ovarian cancer in women. Different hypothesis have been proposed to explain this tissue specificity. One of the most argued hypothesis is the one that proposes a link between BRCA1 and ovarian hormones' action. Much data have been published in the last years pointing to an important role of progesterone receptor (PR) in inducing normal mammary development and also breast cancer formation. This study aimed to search for a functional relationship between BRCA1 and PR in breast cancer cells. We have found that BRCA1 inhibits the transcriptional activity of PR. We have investigated in more detail the mechanism of this effect. BRCA1 and PR interact in vivo in a ligand-independent fashion. Most importantly, BRCA1 alters the ligand-independent and dependent degradation of PR protein through its ubiquitination and this might have a direct effect on the level of PR recruitment on regulated promoters. BRCA1 is recruited to the hormone-responsive regions of PR-target genes and affects the presence of histone deacetylase activity and the level of monoubiquitinated histone H2A, linking BRCA1 action with chromatin status. These findings support a connection between BRCA1, the principal tumour suppressor responsible for familial breast cancer, and the progesterone receptor transcriptional activity. This relationship can be hypothesized to be reflected in the BRCA1-related breast tumourigenesis.<br>Mutaciones germinales en el gen breast cancer susceptibility gene BRCA1 aumentan altamente el riesgo de padecer cáncer de mama y ovario en mujeres. Se han propuesto diferentes hipótesis para explicar esta especificidad de tejido. Una de las hipótesis más argumentadas es la que propone una relación entre BRCA1 y la acción de las hormonas ováricas. En los últimos años se han publicado numerosos datos señalando al papel esencial del receptor de progesterona (PR) en la inducción del desarrollo normal de la mama y en la formación del cáncer de mama. Este estudio pretendía buscar una relación funcional entre BRCA1 y PR en células de cáncer de mama. Hemos demostrado que BRCA1 inhibe la actividad transcripcional de PR. Hemos investigado en más detalle el mecanismo de este efecto. BRCA1 y PR interaccionan in vivo de una manera independiente de ligando. Y lo que es más, BRCA1 altera la degradación independiente y dependiente de ligando de PR a través de su ubiquitinización y esto podría tener un efecto directo en el nivel de reclutamiento de PR en promotores regulados. BRCA1 es reclutado a las regiones de respuesta a hormona de genes diana de PR y afecta la presencia de actividad histona desacetilasa y el nivel de histona H2A monoubiquitinada, estableciendo un enlace entre la acción de BRCA1 y el estado de la cromatina. Estos hallazgos apoyan una conexión entre BRCA1, el principal supresor de tumor responsable del cáncer de mama hereditario, y la actividad transcripcional del receptor de progesterona. Se puede hipotetizar que esta relación se ve reflejada en el proceso de tumorigénesis BRCA1-dependiente.
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Sodre, De Castro Laino Andressa. "Targeting Histone Deacetylases in Melanoma and T-cells to Improve Cancer Immunotherapy." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6144.
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Histone deacetylases (HDACs) are key mediators of gene expression and, thus, major regulators of cell function. As such, HDACs play a role in orchestrating tumor biology, and the use of small inhibitors targeting theses proteins is attractive for the field of cancer therapy. Indeed, several HDAC inhibitors have received FDA-approval for the treatment of malignancies, while a myriad of these compounds continue to be evaluated in clinical trials. Besides their direct impact on tumor growth, HDAC inhibitors have been shown to increase immunogenicity of cancer cells, facilitating generation of a productive immune response against tumors. Immunotherapeutic approaches take advantage of the intrinsic ability of the immune system to manifest an anti-tumor response. Mechanisms of immune escape are often developed by cancer cells, neutralizing activity of the immune system. For example, upregulation of the PD1 ligands PDL1 and PDL2 by tumor cells negatively regulates the anti-tumor functions of PD1-expressing infiltrating T-cells. Importantly, strategies targeting this inhibitory axis have shown outstanding clinical benefit for the treatment of solid and hematological malignancies.
The mechanisms by which HDAC inhibitors modulate tumor and immune cells biology were explored herein. Initially, treatment of melanoma cells with pan- and class I-selective HDAC inhibitors resulted in upregulation of PDL1 and PDL2 molecules. These effects were observed in mouse and human cell lines, as well as in tumor cells resected from metastatic melanoma patients. This upregulation was robust and sustained, lasting at least 96 hours in vitro, and validated in vivo using a B16F10 syngeneic mouse model. Enhanced expression of PDL1 mediated by HDAC inhibitors was found to result from enhanced histone acetylation at the PDL1 gene promoter region. Combination therapy of HDAC inhibition and PD1 blockade was explored in the tumor setting, leading to synergistic effects in terms of reducing melanoma progression and increasing survival of B16F10 melanoma-bearing mice. These data provide a clinical rationale for combination therapy of epigenetic modifiers (e.g. HDAC inhibitors) and PD1 blockade as means to augment cancer immunotherapy, improving patient outcomes.
As a second pillar of this research, the impacts of HDAC-selective inhibition were explored on immune cell biology, since the broad nature of pan-HDAC inhibitors was shown to be detrimental to T-cells in vitro and in vivo. Based on screening assay results, novel implications of treating melanoma patient T-cells ex vivo with the HDAC6-selective inhibitor ACY1215 were investigated. Treatment with this compound was unique among pan- and isotype-selective HDAC inhibitors in modulating T-cell cytokine production and showing minimal impact of T-cell viability. ACY1215 tempered Th2 cytokine production (i.e. IL-4, IL-6 and IL-10), and maintained Th1 effector cytokines (e.g. IFNγ and IL-2). Furthermore, ACY1215 increased expression of surface markers, including CD69 activation marker and ICOS co-stimulatory molecule. In addition, ACY1215 treatment enhanced accumulation of central memory T-cells during ex vivo expansion of tumor infiltrating T-cells harvested from resected tumors of metastatic melanoma patients. Importantly, ACY1215-mediated inhibition improved tumor-killing capacity of T-cells.
These results highlight an unexplored ability of selective HDAC inhibitor ACY1215 to augment T-cell expansion during protocols of adoptive cell therapy. While the discoveries presented here warrant further investigation of cellular and molecular mechanisms associated with ACY1215-treated T-cells, the clinic implications are clear and rapidly translatable.
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Lu, Qiang. "Potent short-chain fatty acid-based histone deacetylase inhibitors as anti-tumor agents." Connect to resource, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1117541292.
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Thesis (Ph. D.)--Ohio State University, 2005.<br>Title from first page of PDF file. Document formatted into pages; contains xix, 116 p.; also includes graphics. Includes bibliographical references (p. 106-116). Available online via OhioLINK's ETD Center
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Ozdarska, Katarzyna. "Synthèses d’inhibiteurs de HDAC et leurs tests biologiques (Cytotoxicité, HDAC inhibition)." Thesis, Reims, 2020. http://www.theses.fr/2020REIMS023.
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L’épigénétique représente les modifications de l’expression génique, sans altérer la séquence nucléique de l'ADN. L'un des mécanismes de régulation est le remodelage de la chromatine qui s’effectue via les histones acétyltransférases et les histones désacétylases (HDAC) permettant ou non la transcription de gènes. Une expression anormale des HDAC est corrélée à de nombreuses maladies (dépendance à l'alcool, inflammation ainsi que les maladies cardiovasculaires et neurodégénératives, cancers…). Il est primordial de cibler la sélectivité d’une isoforme parmi les 11 connues des HDAC zinc dépendantes pour éviter les effets secondaires. Le but de la recherche était de concevoir et de synthétiser de nouveaux composés, de vérifier leur activité inhibitrice vis-à-vis des HDAC de classe I ou II et leur cytotoxicité sur quatre lignées cellulaires: HaCaT, V79-4, SH-SY5Y et PC12. Ainsi, nous nous sommes concentrés sur les pharmacomodulations du ZBG, de l’espaceur et de la tête de molécules connues tels que le MS-275 (sélectif de la classe I des HDAC), les SAHA et TSA (espaceur en C5 ou C6) avec une forte activité inhibitrice vis-à-vis des HDAC, mais non sélectifs. Nous nous sommes concentrés sur les pharmacomodulations de l'HDACI connu modifiant le domaine de liaison au zinc ZBG (sulfonylhydrazide, catéchol), la nature de l’espaceur (alkyl, aryl) et le groupe de reconnaissance de surface (bis-aryl, adamantyl, indolopyridazinone). Une bibliothèque de 57 nouveaux composés a été créée en trois séries. Aucun d'entre eux n'a montré d'activité inhibitrice satisfaisante. Les composés sélectionnés n'ont pas montré d'activité cytotoxique sur les lignées de cellules neuronales. Sur la base de cette recherche, il est possible de créer de nouveaux composés dans la série indolopyridazinone afin de les tester<br>Epigenetics represents changes in gene expression without altering the nucleic sequence of DNA. One of the main mechanisms of regulation of gene expression is chromatin remodeling via histone acetyltransferases and histone deacetylases (HDAC), which may or may not allow gene transcription. An abnormal expression of HDACs is correlated with many diseases (alcohol dependence, inflammation as well as cardiovascular and neurodegenerative diseases, cancers...). It is essential to target the selectivity of one isoform among the 11 known zinc-dependent HDACs to avoid side effects. The aim of the research was to design and synthesize new compounds, verify their inhibitory activity against class I or II HDACs and their cytotoxicity on four cell lines: HaCaT, V79-4, SH-SY5Y and PC12. We focused on the pharmacomodulations of ZBG, the linker and the cap of known molecules such as MS-275 (selective for class I of HDACs), SAHA and TSA (spacer in C5 or C6) with a strong inhibitory activity towards HDACs, but not selective. We concentrated on the pharmacomodulations of known HDACI modifying the zinc binding domain (sulfonylhydrazide, catechol), the nature of the spacer (alkyl, aryl) and the surface recognition group (bis-aryl, adamantyl, indolopyridazinone). A library of 57 new compounds was designed in three series. None of them showed satisfactory inhibitory activity. The selected compounds did not show cytotoxic activity on neuronal cell lines. Based on this research, it is possible to create new compounds in the indolopyridazinone series in order to test them
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Woods, David Michael. "Histone Deacetylases as Targets for Melanoma Immunotherapy." Scholar Commons, 2013. http://scholarcommons.usf.edu/etd/4856.
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Cancer represents the second leading cause of death in the United States. For many malignancies, currently available treatment options offer little long-lasting survival benefits to patients. However, recent studies have shown immunotherapeutic approaches to be an attractive strategy to cancer treatment. While many current immunotherapeutic strategies convey durable responses, such responses are only seen in a minority of patients. An increased understanding of the mechanisms governing tumor immunogenicity and the biology of immune responses is crucial to improving upon the efficacy of current and future cancer immunotherapies. Histone deacetylases (HDACs), enzymes classically associated with regulation of gene expression, have been therapeutic targets in various cancers for several years due to their involvement in cell growth. However, it has become increasingly clear that HDACs are intimately involved in regulating both the immunogenicity of tumor cells and immune response of leukocytes and lymphocytes. In order to expand upon this growing knowledge, the therapeutic efficacy of the pan-HDAC inhibitor LBH589 in the treatment of melanoma was studied. The results presented here demonstrate that LBH589 is a potent inhibitor of growth in a wide variety of melanomas through induction of cell cycle arrest and apoptosis. Additionally, LBH589 increases the immune visibility of melanoma cells by increasing expression of several immune associated cell surface markers (e.g. MHC I, MHC II, CD80, CD86) in addition to upregulating expression of melanoma differentiation antigens. Furthermore, LBH589 treatment of immune cells results in an enhanced pro-inflammatory phenotype of both APCs and T-cells. These combined effects result in better activation of T-cells and ultimately prolonged survival in LBH589 treated, melanoma-baring mice. To further the understanding of the role of individual HDACs in the T-cell response, the biology of the newest HDAC, HDAC11, was further assessed. To this end, it is shown that HDAC11 is differentially expressed in T-cell populations, and expression is rapidly decreased following activation. Utilizing an HDAC11 knockout (HDAC11KO) mouse strain, it is found that both CD4+ and CD8+ T-cells lacking HDAC11 have an enhanced type 1 effector function characterized by increased proliferation and secretion of IL-2, TNF and IFN-γ. Additionally, HDAC11KO CD8+ T-cells have increased expression of both granzyme B and perforin. HDAC11KO T-cells also demonstrate enhanced resistance to inhibition by Tregs and anergy formation. As a possible mechanism for the observed phenotype, it is also demonstrated that HDAC11KO T-cells produce elevated levels of the transcription factors Eomes and T-bet, both at the basal state and post-activation. In vivo, T-cells lacking HDAC11 have a more potent and robust ability to cause GvHD and mediate an enhanced anti-tumor response. Collectively, these results demonstrate that targeting of HDACs is a viable approach to cancer immunotherapy, and that targeting of specific HDACs may be an attractive strategy for optimizing immunotherapy efficacy while minimizing side effects.
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Feng, Chao. "Approaches to the Search of Platinum Anticancer Agents: Derivatizing Current Drugs and Incorporating HDAC Inhibition." Scholarly Commons, 2019. https://scholarlycommons.pacific.edu/uop_etds/3637.
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Platinum-based anticancer drugs, such as cisplatin, carboplatin, and oxaliplatin, have been approved for clinical use worldwide for decades. Despite their enormous success, their widespread application is hindered by either cross-resistance or toxic side effects, including nephrotoxicity and neurotoxicity. The need to overcome these drawbacks has stimulated the search for new platinum-based drugs.
This dissertation will start with the accidental discovery of cisplatin, followed by an introduction of other platinum-based anticancer agents, including the action mechanism, general structures, and development history. Picoplatin is a newer generation of platinum-based anticancer agent. The bulky 2-methylpyridine as a non-leaving group on picoplatin could reduce the detoxification effect caused by thiol-containing species, such as glutathione and metallothionein, thus may grant picoplatin the ability to overcome cisplatin resistance. A convenient synthesis route for picoplatin derivatives has been developed. 11 new picoplatin derivatives have been designed by varying the bulkiness of the non-leaving amine group. All complexes have been characterized by different instrumentations, including MS, 1H NMR, 13C NMR, 195Pt NMR, HMQC, X-ray crystallography, and elemental analysis. Different bioassays, such as DNA binding, cell viability, and cellular accumulation, have been applied to evaluate their efficacy on cisplatin-sensitive ovarian cancer cell line A2780 and cisplatin-resistant ovarian cancer cell line A2780cis. The newly designed picoplatin derivatives show comparable efficacy with that of picoplatin and less resistance compared with cisplatin. The study of picoplatin derivatives laid the foundation toward the research of bifunctional platinum-based anticancer agents by incorporating histone deacetylase (HDAC) inhibition.
Histone acetyltransferase (HAT) and histone deacetylase (HDAC) are a pair of important enzymes in epigenetic regulation. They work in harmony to acetylate and deacetylate histone lysine residues, resulting in a more relaxed or more condensed chromatin structure, respectively. HDAC has been found to be overexpressed in some cancer cells. Since 2006, 5 HDAC inhibitors (HDACi) have entered clinical use for cancer treatment. 19 new HDACi with additional coordination sites on the phenyl cap have been designed, synthesized, and evaluated. A few of the new HDACi show comparable or even better HDAC inhibition than that of Vorinostat (SAHA, the first FDA approved HDACi).
A logical design would involve the installation of HDACi on the platinum center as a non-leaving group ligand. When the bifunctional drug reaches the cancer cell, the synergistic effect could be maintained as the relaxed chromatin structure makes DNA more susceptible to be attacked by the platinum centers, thus increase the anticancer activity and possibly selectivity toward cancer cells. 6 Pt-HADCi conjugates have been designed and synthesized. Dual functions of the new Pt-HDACi have been confirmed by DNA electrophoresis assay and HDAC inhibition assay. One of the Pt-HDACi (CF-101) shows comparable cytotoxicity with cisplatin and less resistance, which could be used as the lead compound for further structural modification and in vivo studies.
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Battini, Vishnu Priya Chowdary. "Accurate splicing of HDAC6 requires Son." Wright State University / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=wright1390306890.
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Linares, Aurélien. "Histone désacétylases, signalisation œstrogénique et cancer du sein : établissement d’outils bioluminescents pour la détection d’inhibiteurs sélectifs de HDAC : expression et rôle de HDAC9 dans les lignées cellulaires de cancer du sein." Thesis, Montpellier 1, 2011. http://www.theses.fr/2011MON13504/document.
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Le récepteur des oestrogènes (RE) peut moduler l’expression de gènes impliqués dans les processus de prolifération et d’apoptose cellulaires. Cette régulation est possible par le recrutement de complexes corégulateurs. Dans ces complexes, l’activité répressive s’explique essentiellement par la présence d’histones désacétylases (HDAC). Cette famille de protéines est composée de 18 membres classés en 4 groupes. Cette répartition est due aux similarités structurales et de fonctions de ces enzymes. Il y a la classe I (HDAC 1, -2, -3, -8), la classe II (HDAC 4, -5, -6, -7, -9, -10) et la classe IV (HDAC 11) qui ont une activité Zn2+ dépendante alors que la classe III (Sirt1-7) recense les HDAC avec une activité NAD+ dépendante. Des résultats récents du laboratoire ont montré, qu’au niveau ARNm, il y avait un important différentiel d’expression de HDAC9 entre les lignées cellulaires de cancer du sein RE positive et négative ou résistante au tamoxifène. Durant ma thèse, j’ai démontré que la régulation de HDAC9, au niveau de son expression, comme au niveau de ses fonctions, affecte la signalisation oestrogénique en modulant l’expression et l’activité transcriptionnelle de REα. De plus, de nombreuses études ont montré l’activité antiangiogénique d’inhibiteurs de HDAC (HDI) à large spectre comme la TSA (Tricostatin A). La conception et l’identification de HDI, potentiellement sélectifs, comme agents anti-tumoraux et/ou anti-métastatique représente une nouvelle approche de thérapie seule ou combinée avec les produits déjà utilisés dans le traitement du cancer. Ainsi, afin d’identifier et caractériser de nouveaux HDI, j’ai établi un outil bioluminescent pour la détection d’inhibiteurs sélectifs de HDAC. Plusieurs lignées cellulaires Gal4-VP16-HDAC ont été générées dans ce but<br>The estrogen receptor (ER) can modulate the gene expression with consequences in the cell proliferation, apoptosis. This modulation is possible by the recruitment of coactivator or corepressor complexes. The repression activity is in particular explained by the histones deacetylases (HDACs). This protein family is composed by eighteen members who have been classified in four groups. These HDACs are subdivided on structural and functional similarities. The class I isoforms (HDACs 1, 2, 3 and 8), class II (HDACs 4, 5, 6, 7, 9, 10) and class IV (HDAC11) are Zn-dependent enzymes, whereas class III HDACs (Sirtuins 1-7) are NAD+-dependent. Recent data from the laboratory have shown, at the mRNA level, there is an enormous expression differential of HDAC9 between breast cancer cell line ER positive and negative or OHT resistant cell line. During my thesis, I demonstrated that the regulations of the HDAC9 on the level of its expression as of its role in the various breast cancer cell lines were implicated in the estrogen signaling. This regulation takes place at the transcriptional level and in the ERet#945; activity.In addition, using broad spectrum HDAC inhibitors (HDIs) such as TSA (Tricostatin A), many studies have shown that these inhibitors had antiangiogenic activity. Thus, the design or the identification of selective and potent HDAC inhibitors as agents anti-tumoral and/or anti-metastatic can emerge in a novel opportunity used alone or in combination with the already existing agents for the treatment of cancers. In order to identify and characterize new HDIs, my thesis works consisted to establish bioluminescent cell lines for screening HDAC inhibitors. Different cell GAL4-VP16-HDACs chimeras' models were generated to determine the selectivity of HDIs for the different HDACs
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Núñez, Álvarez Yaiza. "Role of HDAC11 in muscle cell differentiation and regeneration = Paper de HDAC11 en la diferenciació i regeneració musculars." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/457955.
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HDAC11 is the newest member of the histone deacetylase (HDAC) family and one of the less studied. Its expression was described to be enriched in skeletal muscle tissues from the first moment of its discovery, yet now after 15 years, its roles in myogenesis remain unknown. We started this thesis by analyzing the expression changes of all HDAC’s’ members between proliferation and early differentiation conditions, which constitutes a crucial cell fate point in which cells have to decide whether to continue proliferating or enter to irreversible G0 arrest state to differentiate. With this analysis, we found HDAC11 as the HDAC family member the most upregulated in the skeletal muscle differentiation process. By CRISPR/Cas9 knock-in tagging of endogenous HDAC11, we show that HDAC11 protein levels are absent in proliferating cells and increased through differentiation. The silencing of HDAC11 in proliferation conditions is mediated, at least in part, by class I HDAC’s deacetylation of MYOD. In differentiation conditions, acetylated MYOD and myogenin, the two master regulators of muscle differentiation, bind to HDAC11 promoter regions and trigger its expression.
HDAC11 deficient myoblasts did not present major alterations in cell proliferation or differentiation capacities but show reduced fusion ability. Genome-wide transcriptomic analysis of differentiating HDAC11 deficient myoblasts revealed an upregulation of genes involved in proliferation and a decreased expression of genes involved in muscle contraction, suggesting a delayed entry in G0 irreversible arrest state. Our ChIP results suggest that HDAC11 would mediate repression of proliferation related genes by deacetylation of H3 in their promoter regions. Moreover, HDAC11 expression is also highly expressed in additional G0 states, like in reversible arrested quiescent satellite cells.
In skeletal muscle tissues, HDAC11 is higher expressed in fast muscles than slow ones, especially in males. The analysis of HDAC11 deficient mice concludes that HDAC11 absence do not cause major alterations in muscle development, adult myofiber growth or fiber type composition in basal conditions. In regeneration conditions, HDAC11 deficient mice show advanced regeneration capacity at 7 days post injury, probably mediated at least in part, by an increased expression of Il-10 by HDAC11 deficient macrophages.
Finally, we show that HDAC11 upregulation through differentiation is conserved in human myoblast and its expression is reduced in rhabdomyosarcoma cells, which present impaired differentiation capabilities.
Altogether, our results place HDAC11 as a new epigenetic regulator in in vitro an in vivo myogenesis.<br>HDAC11 és el membre més recentment descobert de la família de deacetilases d'histones (HDAC) i un dels menys estudiats. En el moment del seu descobriment es va veure que estava altament expressada en teixits de múscul esquelètic encara que després de 15 anys, les seves funcions en la miogènesi resten encara desconegudes.
Vam començar aquesta tesi analitzant els canvis d'expressió de tots els membres de la família HDAC entre les condicions de proliferació i diferenciació primerenca, un moment crucial on les cèl·lules han de decidir si continuen dividint-se o entren en l'estat d'aturada irreversible G0 per diferenciar-se. Amb aquesta anàlisi vam trobar HDAC11 com el membre de la família HDAC que augmentava més la seva expressió en aquest procés. Amb la tècnica d'enginyeria genètica CRISPR/Cas9 vam aconseguir inserir un epítop en el locus genòmic de HDAC11, que ens permeté demostrar que la proteïna HDAC11 està absent en condicions de proliferació i augmenta amb la diferenciació. El silenciament de l'expressió de HDAC11 durant la proliferació està mitjançada, almenys en part, per la deacetilació de MYOD per part de la classe I de HDACs. Durant la diferenciació, MYOD acetilat i miogenina, els dos reguladors responsables d’iniciar la diferenciació muscular, s'uneixen al promotor de HDAC11 i activen la seva expressió.
Els mioblasts deficients en HDAC11 no presenten greus alteracions en la proliferació cel·lular o en la seva capacitat de diferenciar-se però mostren una reduïda capacitat de fusió. L'estudi transcriptòmic a escala global de mioblasts deficients en HDAC11 va revelar una sobreexpressió de gens involucrats en la proliferació cel·lular i una reducció en l'expressió de gens amb funcions en la contracció muscular, suggerint una entrada més tardana en la fase G0 d'aturada irreversible. Els nostres resultats de ChIP suggereixen que HDAC11 podria intervindre en la repressió dels gens involucrats en la proliferació cel·lular mitjançant la deacetilació de les histones H3 dels seus promotors. A més, l'expressió d'HDAC11 també és alta en estats addicionals de G0 com l'arrest reversible de les cèl·lules satèl·lit quiescents.
En teixits de múscul esquelètic, HDAC11 està més expressada en músculs ràpids que lents, especialment en mascles. L'anàlisi de ratolins deficients en HDAC11 conclogué que l'absència de HDAC11 no causa greus alteracions en el desenvolupament muscular, el creixement de miofibres adultes o en la composició en tipus de fibres en condicions basals. Durant la regeneració muscular, els ratolins deficients en HDAC11 mostren un avanç en la seva capacitat de regeneració 7 dies després de la lesió, probablement mitjançat en part per un increment en l’expressió de Il-10 per part dels macròfags deficients en HDAC11.
Finalment, mostrem que l’augment d’expressió de HDAC11 està conservat en la diferenciació de mioblasts humans i que la seva expressió està reduïda en rabdomiosarcoma, patologia tumoral que presenta un impediment en la diferenciació muscular. En conjunt, els nostres resultats situen HDAC11 com un nou regulador epigenètic en la miogènesi in vitro i in vivo.
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Darcy, Michael. "Characterization of HDAC4's role in brain." Tallahassee, Florida : Florida State University, 2010. http://etd.lib.fsu.edu/theses/available/etd-12082009-143750.
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Thesis (Ph. D.)--Florida State University, 2010.<br>Title and description from dissertation home page viewed on July 26, 2010. Advisor: Charles C. Ouimet, Florida State University, College of Arts and Sciences, Dept. of Biological Science. Includes bibliographical references.
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Vieson, Miranda Diane. "Selective HDAC6 Inhibition in Systemic Lupus Erythematosus." Diss., Virginia Tech, 2017. http://hdl.handle.net/10919/74872.
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Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by abnormalities in multiple components of the immune system resulting in progressive damage to multiple organs. Current treatments for SLE are often intensive and result in side effects and the potential for continued flares and progression of disease. Histone deacetylase (HDAC) enzymes control multiple cellular functions by removing acetyl groups from lysine residues in various proteins. HDAC inhibitors have been investigated as a potential treatment for SLE with promising results, however selective HDAC6 inhibition (HDAC6i) has become a leading candidate for pharmacologic inhibition to reduce the potential for side effects. We hypothesize that HDAC6i will decrease SLE disease by targeting substrates of HDAC6 in multiple components of immunity and organ systems. NZB/W mice were treated with ACY-738 or ACY-1083, followed by evaluation of multiple disease parameters and mechanisms involved in disease pathogenesis within the kidney, bone marrow, and spleen. Within the kidney, HDAC6i decreased glomerular pathology scores, proteinuria, and IgG and C3 deposition. Within glomerular cells, HDAC6i increased alpha-tubulin acetylation and decreased nuclear NF-κB. Within the spleen, there was a dose-dependent decrease in the frequency of Th17 cells and a mild decrease in the frequency of Treg cells. Concurrently, there were decreased levels of IL-12/IL-23 and minimal decreases in TGF-β in the serum. Within the bone marrow, B cell development through Hardy fractions exhibited accelerated progression through later stages as NZB/W mice aged. This accelerated progression may allow B cells to bypass important regulatory checkpoints in maintaining immune tolerance and contribute to autoimmunity. Treatment with an HDAC6i corrected the aberrant B cell development in the bone marrow and RNAseq analysis unveiled six genes (Cebpb, Ccr9, Spib, Nfil3, Lgals1, and Pou2af1) that may play a role in the aforementioned abnormalities. Overall, these findings show that HDAC6i decreased disease in NZB/W mice by targeting multiple components of the immune response, including glomerular cells, T cell subsets in the spleen, and bone marrow B cells. In conclusion, selective HDAC6i is an excellent candidate for pharmacologic therapy for SLE because it targets multiple immune abnormalities involved in SLE pathogenesis while remaining selective and safe.<br>Ph. D.
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Boyault, Cyril. "Fonctions ubiquitine-dépendantes de la déacétylase HDAC6." Université Joseph Fourier (Grenoble), 2006. http://www.theses.fr/2006GRE10230.
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Avant le début de ma thèse, le laboratoire avait découvert et caractérisé HDAC6, une histone déacétylase atypique qui possède deux domaines déacétylase et peut interagir directement avec l'ubiquitine, grâce à son domaine ZnF-UBP. De plus, le laboratoire avait montré que HDAC6 interagit avec UFD3/PLAP, un régulateur du turnover de l'ubiquitine, et p97/VCP, un homologue murin de la chaperonne de levure Cdc48p. Cependant, aucune fonction biologique n'était connue pour HDAC6, notamment dans la voie d'ubiquitination des protéines. Nous avons tout d'abord observé que la surexpression de HDAC6 ralenti la dégradation des protéines polyubiquitinées, via son ZnF-UBP, son domaine de liaison à l'ubiquitine. Grâce a une série d'expériences, nous avons pu montrer que les complexes HDAC6-p97/VCP régulent directement la stabilité des protéines poly-ubiquitinées. L'accumulation intracellulaire de protéines poly-ubiquitinées peut être toxique pour les cellules si aucune réponse cellulaire n'est engagée. En réalité, une telle accumulation active le facteur de transcription Heat Shock Factor 1 (HSFI) afin de promouvoir la survie de la cellule. Grâce à ces considérations, nous avons découvert que HDAC6 et p97/VCP contrôlent la réponse cellulaire à l'accumulation de protéines poly-ubiquitinées<br>At the start of my Ph. D. , the lab had discovered and characterized HDAC6, an unusual deacetylase that possesses two deacetylase domains and directly binds to ubiquitin. Moreover, the lab had found that HDAC6 interacts with UFD3/PLAP, a regulator ofubiquitin turnover, and VCP, a mouse homologue of the chaperone Cdc48. However, nothing was known about HDAC6 biological function, especially its role in the ubiquitination pathway. We first observed that HDAC6 over-expression slows down the degradation ofpolyubiquitinated protein, via ZnF-UBP, its ubiquitin binding domain. Through a series of experiments, we have shown that, actually, HDAC6-VCP complex directly regulates the level of poly-ubiquitinated proteins. We then discovered that HDAC6 controls the cellular response triggered by the accumulation of poly-ubiquitinated proteins, and have unraveled mechanisms involved in this control. The accumulation of poly-ubiquitinated proteins could be toxic for cells if no cellular response is engaged. Moreover, it has been well-known for about ten years that such accumulation activates the transcription factor Heat Shock Factor 1 (HSFI) to promote cellular survival. We found that, in the absence of stress, HDAC6 and HSF 1 are in a complex with VCP and HSP90. However, when the pool ofpoly-ubiquitinated proteins increases, such as during heat shock, HDAC6 is released from the complex in a ubiquitin and ZnF-UBP dependent manner. Such a release then enables VCP to activate HSFI. Ln conclusion, we propose that HDAC6-p97/VCP complexe appears as a master regulator during both poly-ubiquitinated protein management and cellular stress response engagement
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Shen, Jie. "STUDIES ON GLYCOPHARMACEUTICALS, HDACI AND NO-DONORS." The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1207080109.
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Ratti, Francesca. "Role of HDAC6 in Skeletal Muscle Atrophy." Thesis, Lyon, École normale supérieure, 2014. http://www.theses.fr/2014ENSL0887.
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HDAC6 est une histone déacétylase hautement conservée, principalement cytoplasmique. Contrairement à d'autres désacétylases, HDAC6 a une spécificité de substrat unique pour les protéines non - histones . Outre les domaines de désacétylation, HDAC6 contient également un domaine de liaison à l'ubiquitine , qui relie HDAC6 de la voie ubiquitine / protéasome .L’atrophie du muscle squelettique est une condition sévère de perte progressive de masse musculaire au cours de certaines maladies telles le cancer, le diabète, le SIDA ou également immobilizations prolongées. Le contrôle de la masse musculaire est sous la dépendance d’un équilibre entre les processus anaboliques et cataboliques. L’atrophie se caractérise par une augmentation substantielle de la dégradation des protéines par le système ubiquitine-protéasome, causée par l'expression d'une série de gènes spécifiques, les atrogenes . Un des atrogenes induits plus spectaculaire est le muscle spécifique de l'ubiquitine ligase E3 MAFbx/Atrogin-1, qui prend soin de la dégradation de MyoD et de eIF3 -f. La dégradation de ces deux protéines inhibe l'expression de gènes et la traduction myotrophiques empêchant le remplacement de protéines dégradées.Récemment, nous avons identifié l’Histone Deacetylase 6 (HDAC6) comme un nouvel atrogène. L’expression de HDAC6 augmente au cours de l’atrophie musculaire, à la fois chez la souris et l’homme, à travers un mécanisme FOXO3 -dépendante. La déplétion de cet enzyme in vivo (electroporation de l’shRNA contre HDAC6 dans des muscle squelettiques de souris ou analyse de souris invalidées pour ce gène) protège contre l’atrophie. De plus, l’inhibition de HDAC6 après déclenchement de l’atrophie peut aussi atténuer le phénotype. Lors de la caractérisation du mécanisme d’action de HDAC6, nous avons montré que HDAC6 intéragit avec MAFbx et que elle est nécessaire pour l’ubiquitination de MyoD par MAFbx. Nos résultats montrent que la surexpression d’un mutant MyoD resistant à la degradation par MAFbx protège contre l’atrophie provoqué par la denervation.. De plus, certaines données préliminaires indiquent une implication de HDAC6 dans la dégradation de eIF3-f et dans le processus de autophagy dans le tissu musculaire , révélant une double rôle de HDAC6 dans le muscle squelettique .Ces preuves suggèrent que HDAC6 représente potentiellement une cible utile pour des traitements curatifs<br>HDAC6 is a highly conserved histone deacetylase, mostly cytoplasmic. Unlike other deacetylases, HDAC6 has unique substrate specificity for non-histone proteins. Besides the deacetylation domains, HDAC6 also contains an ubiquitin-binding domain, which links HDAC6 to the ubiquitin/proteasome pathway. Skeletal muscle atrophy is a severe condition of muscle mass loss occurring during aging or in many clinical disorders as cancer, diabetes and AIDS. The maintenance of muscle mass is subtly controlled by an equilibrium between catabolic and anabolic processes. Muscle atrophy results as a partial suppression of protein synthesis and a substantial increase of protein breakdown by the ubiquitin-proteasome system, caused by the expression of a series of specific genes, the atrogenes. One of the atrogenes induced more dramatically is the muscle specific E3 ubiquitin ligase MAFbx/Atrogin-1, which takes care of the degradation of MyoD and of eIF3-f. Degradation of those two proteins inhibits expression of myotrophic genes and translation preventing the replacement of degraded proteins.We identified HDAC6 as a new atrogene. HDAC6 expression is up regulated during muscle atrophy in mouse and human through a mechanism FoxO3-dependent. In vivo depletion of this enzyme by shRNA electroporation or homologous recombination gives protection against atrophy and its inhibition during atrophy can partially reverse the muscle wasting phenotype. HDAC6 can interact with MAFbx and is required for MAFbx-mediated degradation of MyoD. According to our results, forced expression of a MyoD mutant resistant to HDAC6 and MAFbx dependent degradation prevents muscle wasting induced by denervation. Furthermore, some preliminary data show an involvement of HDAC6 in the degradation of eIF3-f and in the autophagy process in muscle tissue, revealing a double role of HDAC6 in skeletal muscle.These evidences suggest that HDAC6 potentially represents a valuable target for curative treatments
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Khan, Omar Ali. "HR23B, a biomarker for HDAC inhibitors." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:9cd76c0b-e70e-43f7-a92d-a99f403a077e.
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As our understanding of cancer biology increases and novel therapies are developed, an increasing number of predictive biomarkers are becoming clinically available. Aberrant acetylation has been strongly linked to tumourigenesis and the modulation of acetylation through targeting histone deacetylase (HDAC) has led to the introduction of many HDAC inhibitors. To date, two have had regulatory approval for the treatment of cutaneous T cell lymphoma (CTCL). Modifications in chromatin control underpin the mechanism of action of HDAC inhibitors. A genome wide loss-of-function screen identified HR23B as a gene that governs sensitivity to HDAC inhibitors. HR23B shuttles ubiquitinated cargo proteins to the proteasome and elevated levels may contribute to cell death mediated by this pathway. It also governs cell sensitivity to drugs that act directly on the proteasome. HDAC inhibitors influence proteasome activity and there may be a synergistic interaction with proteasome inhibitors. HR23B and HDAC6 interact and HDAC6 may be a negative regulator of apoptosis and a positive regulator of autophagy and through its ability to down-regulate HR23B, may impact on the cellular outcome of HDAC inhibitor treatment. Expression of HR23B has been correlated with clinical response to HDAC inhibitors in a retrospective analysis of CTCL patients. The tissue expression of HR23B and the autophagy marker LC3 has been investigated and there may be a reciprocal relationship in their expression in some tumours which may provide prognostic information and patients with low HR23B expression but high levels of autophagy appear to have a particularly poor prognosis. Well designed, biomarker-driven prospective clinical trials are needed to clarify the predictive and prognostic roles of HR23B.
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Vidal, Laliena Miriam. "La HDAC3 regula l’estabilitat de la ciclina A." Doctoral thesis, Universitat de Barcelona, 2012. http://hdl.handle.net/10803/83515.
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El cicle cel•lular consta d’una sèrie de fases que donen lloc a dues cèl•lules filles genèticament idèntiques. Les diferents fases del cicle cel•lular (G1, S, G2, la mitosi i la citocinesi) són regulades per diferents complexes CDKs/ciclines. Aquests complexes estan formats per una subunitat catalítica, CDK i una subunitat reguladora, la ciclina. Els complexes CDK4-6/ciclina D regulen la transició G1/S, els complexes CDK2/ciclina A-E regulen la fase S i els complexes CDK1/ciclina A-B regulen la fase M. En aquesta tesi s’ha estudiat la regulació d’una d’aquestes ciclines, la ciclina A. Aquesta proteïna realitza funcions durant la fase S i la fase G2/M del cicle cel•lular, com per exemple, la seva implicació en l’inici i progressió de la replicació del DNA, evitar la re-replicació, regular la formació dels centrosomes, la condensació dels cromosomes i el trencament de l’embolcall nuclear. També, però s’han descrit funcions independents de CDKs, com per exemple la regulació de la invasió cel•lular a través de la via de senyalització de RhoA.
La inhibició de la ciclina A provoca un retard en la metafase i anafase, causant un retard en la separació de les cromàtides germanes. En canvi, la sobreexpressió de la ciclina A provoca un avançament en la fase S. De la mateixa manera, s’han trobat nivells elevats de la ciclina A en certs tumors de mama, colon, pròstata,… A més, l’obtenció de ratolins knockout de ciclina A causa letalitat embrionària. En resum l’alteració de l’expressió de la ciclina A causa un desajustament durant el cicle cel•lular. Així doncs, els mecanismes que controlen la regulació de la ciclina A són importants pell bon funcionament de la proteïna a cada fase del cicle cel•lular.
La ciclina A es degrada durant la prometafase. La causa de la seva degradació és l’acetilació per l’acetilasa P/CAF a quatre residus de lisina, els quals causen la seva ubiquitinització i posterior degradació per la via del proteasoma. El balanç acetilació/deacetilació està controlat per l’acció oposada d’acetilases i deacetilases. L’actual treball ha demostrat que la ciclina A interacciona amb la HDAC3, un proteïna que pertany a la classe I de la família de les HDACs clàssiques. Hem comprovat la interacció directa de la ciclina A i la HDAC3 a través del domini N-terminal de la ciclina A, el qual és important per a la degradació de la ciclina A. A més, aquestes proteïnes interaccionen durant les fases G1/S i G2/M. La sobreexpressió de la HDAC3 causa una disminució de l’acetilació de la ciclina A, així com la deleció de la HDAC3, provoca un increment en el seu estat d’acetilació, i per tant, una disminució de la vida mitra de la ciclina A. Finalment, hem comprovat que la HDAC3, a la vegada, també es degrada durant la mitosi, i estudis inicials en indiquen que possiblement la fosforilació de la HDAC3 regularia la seva estabilitat.
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Palleti, Janardhan Harish P. "Histone Deacetylase 3 (HDAC3) Regulates Lymphatic Vascular Development." eScholarship@UMMS, 2018. https://escholarship.umassmed.edu/gsbs_diss/1001.
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Cardiovascular disease continues to be the leading cause of morbidity and mortality worldwide with an estimated 17 million annual deaths. A majority of cases are attributed to disease affecting the vascular system including arterial, venous and lymphatic vessels. Despite progress in understanding the molecular bases of vascular development and disease, the role of chromatin modifying enzymes in vascular processes remains ill defined. Here we show that the histone-modifying enzyme Hdac3 is a critical regulator of lymphatic vascular development. Endothelial specific loss of Hdac3 in mice affects the development of lymphovenous and lymphatic valves resulting in aberrant blood lymph separation, lymphedema and complete lethality. We demonstrate that Hdac3 functions in a flow responsive manner to regulate the expression of Gata2, a transcription factor essential for lymphatic valve development. In response to flow, transcription factors Tal1, Ets1/2 and Gata2 recruit Hdac3 to an evolutionarily conserved intragenic enhancer of Gata2 gene. In turn, Hdac3 recruits p300, a histone acetyl transferase, to render activation of the Gata2 enhancer, and thus promotes Gata2 transcription. Together, our findings demonstrate the molecular basis by which cell extrinsic and intrinsic cues cooperate to regulate lymphatic development.
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Gilquin, Benoît. "Etude de la déacétylase HDAC6 : une enzyme multifonctionnelle." Université Joseph Fourier (Grenoble), 2005. http://www.theses.fr/2005GRE10242.
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L'histone déacétylase HDAC6 est une enzyme multifonctionnelle possédant deux domaines déacétylases en tandem et un domaine fixant l'ubiquitine. Localisée exclusivement dans le cytoplasme, cette protéine peut déacétyler les microtubules acétylés et participer à la prise en charge des protéines ubiquitinées lors de la formation d'agrésomes. Elle possède également une activité sur d'autres substrats comme les histones ou HSP90, et elle contribue à divers processus cellulaires. Le travail présenté dans cette thèse décrit un rôle supplémentaire de cette déacétylase dans la réponse après un stress. Il vise à comprendre comment HDAC6 participe dans les mécanismes d'activation des gènes HSPs, et dans les processus de récupération cellulaire à la suite d'un choc thermique. La découverte d'un nouveau domaine nommé SE14 chez la protéine HDAC6 humaine, présente un dispositif supplémentaire de régulation nucléocytoplasmique pour cette protéine. Ce domaine permet la rétention dans le cytoplasme de cette protéine en renforçant le mécanisme d'export nucléaire. A coté de ce contrôle, le fonctionnement des deux domaines déacétylases est analysé. Des expériences in vitro et in vivo confirment l'importance de l'arrangement spatial des deux domaines dans la réaction de déacétylation. Finalement, ce travail montre que la protéine HDAC6 intervient lors de la différenciation ostéoclastique. Par son activité catalytique sur les microtubules acétylés et grâce à son interaction avec l'effecteur mDIA2, cette déacétylase est impliquée dans la maturation des ostéoclastes<br>HDAC6 is a multifunctional enzyme with two tandem catalytic domains and an ubiquitin binding domain. Mainly cytoplasmic, HDAC6 is associated with microtubules, and deacetylates tubulin on lysine 40. Furthermore, cellular management of misfolded proteins and aggresomes is modulated by HDAC6 action. This protein also regulates the acetylation of various proteins, like histones or HSP90, and is involved in several cellular processes. First of all, my work describes additional functions of HDAC6 in stress response. I show that HDAC6 controls HSPs genes activation and the cellular recovery process within the context of cellular stress response. Then the discovery of SE14 domain in the human HDAC6 is an original aspect of this study. This domain is a key element in the human HDAC6 retention in the cytoplasm. Moreover in vitro and in vivo experiences have shown that integrity of both deacetylation domains is required for HDAC6 activity. Finally, this work shows that HDAC6 is involved in osteoclast differentiation. Indeed HDAC6 interacts with mDIA2 and is probably involved in the rearrangement of the cytosqueletton during osteoclast maturation
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Gao, Chengzhuo. "Mechanisms Underlying the Regulation and Functions of HDAC7." Case Western Reserve University School of Graduate Studies / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1213890889.
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Morey, Ramonell Lluís. "Chromatin alterations imposed by the oncogenic transcription factor PML-RAR." Doctoral thesis, Universitat Pompeu Fabra, 2008. http://hdl.handle.net/10803/7138.
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En mamíferos, así como en plantas, mutaciones en AND helicasas/ATPasas del la família SNF2, no solo afectan a la estructura de la cromatina, sino que también afectan al patrón global de la metilación del ADN. Sugiriendo una relación funcional entre la estructura de la cromatina y la epigenética. El complejo NuRD, el cual posee una ATPasa de la familía SNF2, está relacionado con la represión de la transcripción y en el remodelamiento de la cromatina. Nuestro laboratorio demostró que la proteína leucémica PML-RARα reprime la transcripción de sus genes diana por el reclutamiento de DNMTs y el complejo PRC2. En esta tesis, demostramos una relación directa del complejo NuRD en la represión génica y en los cambios epigenéticos en la leucemia promielocítica aguda (APL). Mostramos que PML-RARα se une y recluta NuRD a sus genes diana, incluyendo el gen supresor de tumores RAR2, facilitando que el complejo de Polycomb se reclute y metile la lisina 27 de la histona H3. Tratamiento con Acido Retinóico (RA), el qual se utiliza en pacientes, reduce la ocupación de NuRD en células leucémicas. Eliminando NuRD no solo provoca que las histonas no se deacetilen y que la cromatina no se compacte, sino que también provoca que tanto la metilación del ADN y de las histonas no se produzca, así como la represión génica del gen RAR2, favoreciendo la diferenciación celular. Nuestros resultados caracterizan un nuevo papel del complejo NuRD en el establecimiento de los patrones epigenéticos en APL, demostrando una relación esencial entre la estructura de la cromatina y epigenética durante el desarrollo de la leucemia, pudiéndose aplicar a la terapia de esta enfermedad.<br>In mammals, as in plants, mutations in SNF2-like DNA helicases/ATPases were shown to affect not only chromatin structure but also global methylation patterns, suggesting a potential functional link between chromatin structure and epigentic marks. The SNF2-like containing NuRD complex is involved in gene transcriptional repression and chromatin remodeling. We have previously shown that the leukemogenic protein PMLRARα represses target genes through recruitment of DNMTs and Polycomb complex. In this thesis, we demonstrate a direct role of the NuRD complex in aberrant gene repression and transmission of epigenetic repressive marks in acute promyelocytic leucemia (APL). We show that PML-RARα binds and recruits NuRD to target genes, including to the tumor-suppressor gene RAR2. In turn, the NuRD complex facilitates Polycomb binding and histone methylation at lysine 27. Retinoic acid treatment reduced the promoter occupancy of the NuRD complex. Knock-down of the NuRD complex in leukemic cells not only prevented histone deacetylation and chromatin compaction, but also impaired DNA and histone methylation as well as stable silencing, thus favoring cellular differentiation. These results unveil an important role for NuRD in the establishment of altered epigenetic marks in APL, demonstrating an essential link between chromatin structure and epigenetics in leukemogenesis that could be exploited for therapeutic intervention.
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Román, González Lidia. "Role of Histone Deacetylase HDAC7 in B Lymphocyte Biology." Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/132909.
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Within the hematopoietic system, all mature blood cells are generated. Every differentiation step is characterized by the activation of a new, lineage specific, genetic program and the extinction of the previous one. To date, the contribution of transcription factors in positively regulating these distinct differentiation processes is well established. However, the mechanisms by which transcription factors mediate the gene transcriptional silencing is poorly understood. In this PhD project we tried to elucidate the molecular mechanisms by which histone deacetylases (HDACs) mediate gene transcriptional silencing in B lymphocyte Development. In particular, we decided to study the potential contribution of HDAC7 during B lymphopoiesis. To achieve our objective, we performed a biochemical-genome wide assay by using a highly efficient immune reprogramming system, followed by an in vivo approach by generating conditional knock-out mouse models. For the first objective, we have taken advantage of recently highly efficient cellular reprogramming system consisting of a pre-B cell line modified to express an estradiol induble form of C/EBPα allowing its conversion into functional macrophages (Bussmann, 2009). We demonstrated that among all class IIa HDACs, HDAC7 showed a lymphoid lineage specific expression pattern during transdifferentiation. Re-expression of HDAC7 interfered with the macrophage gene transcriptional program, by blocking the induction of key macrophage genes related to immune, inflammatory response and phagocytosis. HDAC7 interacted with MEF2C and is recruited to the promoters of macrophage genes, leading to their transcriptional repression. Finally, by generating conditional knock-out mice for a specific deletion of HDAC7 in the hematopoietic system, we demonstrated that HDAC7-deficient mice showed a highly relevant block in B cell development at pro-B cell stage. HDAC7 specifically interacted with MEF2C, resulting in the repression of non-lymphoid genes. The absence of HDAC7 resulted in a significant up-regulation of relevant genes related to important biological processes and macrophage functions, such as ubiquitination, cell cycle and signal transduction. In conclusion, we demonstrated that among class IIa HDACs, HDA7, through its interaction with other transcription factors, such as MEF2C, acts as a potential transcriptional repressor in B lymphocyte Biology by repressing lineage inappropriate genes.<br>El desarrollo de células B es el resultado de varios procesos de especificación, compromiso y diferenciación, cada uno de los cuales se caracterizan por la activación de un nuevo programa de transcripción génica y la extinción del anterior. Hasta la fecha, la regulación positiva durante el desarrollo de células B llevada a cabo por factores de transcripción específicos está bien establecida. Sin embargo, los mecanismos por los cuales los factores de transcripción median procesos de represión de genes inapropiados de otros linajes celulares para adquirir y mantenerla identidad celular son vagamente conocidos.
El objetivo principal de este proyecto de tesis es investigar los mecanismos de represión transcripcional durante el desarrollo de linfocitos B. Las histonas desacetilasas (HDACs) de clase IIa han emergido como moduladores cruciales de la transcripción génica en numerosos procesos de desarrollo y diferenciación celular.
De entre todas las enzimas que conforman esta familia, nos centramos en las clase IIa por dos razones fundamentales. En primer lugar, las HDACs de clase IIa se expresan de manera específica de tejido y están implicadas en numerosos procesos de diferenciación celular. En segundo lugar, las HDACs de esta sub‐familia contienen un dominio N‐terminal que media su interacción con factores de transcripción específicos de tejido (como miembros de la familia MEF2), mediando así su acción como co‐represores transcripcionales.
Para lograr nuestro objetivo principal, hemos realizamos dos abordajes experimentales: una aproximación experimental in vitro mediante el uso de un sistema de reprogramación celular, y una aproximación in vivo mediante la generación de un modelo de ratón mutante para HDAC7.
Para estudiar la contribución potencial de las HDACs de clase IIa en la reprogramación de células pre‐B a macrófagos, hemos utilizado un sistema de reprogramación celular que consiste en una línea de células B genéticamente modificadas que se transdiferencian en macrófagos funcionales tras la adición de β‐estradiol (Bussmann, 2009). Hemos demostrado que, a diferencia de las otras HDACs de clase IIa, HDAC7 presenta un patrón de expresión específico de linaje linfoide. Es importante destacar que la re‐expresión de HDAC7 interfiere con la adquisición el programa transcripcional de genes característicos de macrófagos, tales como genes relacionados con la respuesta inmunológica y la fagocitosis, y suprime funciones cruciales de los macrófagos, como la capacidad para fagocitar bacterias y la respuesta celular a endotoxinas. Desde un punto de vista mecanístico, HDAC7 interacciona con MEF2C y es reclutado a los promotores de genes de macrófagos, dando lugar a su represión transcripcional.
Para estudiar el papel de HDAC7 durante el desarrollo de células B, hemos generado un modelo de ratón condicional para delecionar HDAC7 de manera específica en progenitores de células B (células por‐B). Nuestros resultados demuestran que los ratones deficientes en HDAC7 muestran un bloqueo significativo del desarrollo de células B en el estadio celular pro‐B, indicando que HDAC7 es un represor transcripcional esencial en la formación de linfocitos B. Desde un punto de vista mecanístico, HDAC7 es reclutada a sitos de unión para MEF2C localizados en los promotores de genes inapropiados de linaje en células pro‐B. También hemos demostrado que la ausencia de HDAC7 resulta en la activación de genes relevantes característicos de macrófagos y linfocitos T.
En conclusión, hemos identificado HDAC7 como un nuevo regulador esencial en el desarrollo de linfocitos B.