Дисертації з теми "H3K9ac"
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Hache, Antoine. "Molecular basis of transcriptional dysregulations in the spinocerebellar ataxia type 7, a neurodegenerative polyglutamine disorder." Thesis, Strasbourg, 2020. http://www.theses.fr/2020STRAJ083.
SCA7 is a genetic disorder whose one of its main symptoms is a progressive loss of visual acuity which can ultimately lead to blindness. The mutation responsible for this disease is an unstable CAG expansion within ATXN7, a gene encoding a subunit of the SAGA complex, a co-activator of the RNA polymerase II. Previous studies performed on transgenic mouse models highlighted a neuronal identity loss of the photoreceptors at the morphological, functional and molecular levels. During my PhD a characterization of a new SCA7 knock-in mouse model was performed. This model, which expresses the mutated genes at endogenous level recapitulates the retinal impairments observed in transgenic models and in patients. A transcriptomic (RNA-seq) and epigenomic (ChIP-seq) analyses were performed on this model and highlight global acetylation defects on lysine 9 and 27 of histone H3 (H3K9ac and H3K27ac). Moreover, investigations on non-coding RNAs identified the presence of enhancer RNAs (eRNAs) on photoreceptor specific genes such as Rho. These eRNAs, which were never described before, undergo a downregulation in symptomatic SCA7 mice
Beyer, Susanne [Verfasser], and Udo [Akademischer Betreuer] Jeschke. "Immunhistochemische Untersuchung der Expression von H3K9ac, H3K4me3 und GR an Zervix-Karzinom-Präparaten sowie deren prognostische Analyse / Susanne Beyer ; Betreuer: Udo Jeschke." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2020. http://d-nb.info/1209472627/34.
Rifai, Khaldoun. "Etude des modifications épigénétiques en fonction de l'agressivité du cancer sporadique du sein : l'implication de l'histone désacétylase SIRT1 dans la progression tumorale." Thesis, Université Clermont Auvergne (2017-2020), 2018. http://www.theses.fr/2018CLFAS011/document.
With 59,000 new cases in 2017, breast cancer is the most frequently diagnosed cancer among French women, and poses a real public health problem in France, but also worldwide. It is well established that the complexity of carcinogenesis involves profound epigenetic deregulations that contribute to the tumorigenesis process. Deregulated H3 and H4 acetylated histone marks are amongst those alterations. Acetylation and deacetylation are major post-translational protein modifications that regulate gene expression and the activity of a myriad of oncoproteins. Aberrant deacetylase activity can promote or suppress tumorigenesis in different types of human cancers, including breast cancer. The deacetylase SIRT1 and the acetyltransferase TIP60 are 2 antagonistic epigenetic enzymes that are well implicated in apoptosis, gene regulation, genomic stability, DNA repair, and cancer development. In this manuscript, we identified the dysregulation of the histones H3 and H4 acetylation profiles in different molecular subtypes of sporadic breast cancer, and investigated the involvement of SIRT1 and TIP60 in breast tumorigenesis. First, we highlighted the roles of SIRT1 and TIP60 as potential prognostic biomarkers by revealing their differential expression patterns depending on breast cancer aggressiveness. Then, we demonstrated their differential epigenetic regulation of histone targets according to molecular subtype, and revealed their modulation of the H3K4ac epigenetic marker. Moreover, Epi-drugs mediated inhibition of these 2 enzymes has proven to be an effective strategy in the treatment of cancer. Thus, this work highlights the potential use of SIRT1 and TIP60 as epigenetic therapeutic targets for sporadic breast cancer
Audergon, Pauline Nicole Clotilde Beatrice. "Restricted epigenetic inheritance of H3K9 methylation." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/16212.
Ferguson, Fleur Marcia. "Molecular recognition in the BAZ2B bromodomain: histone H3K14ac complex : biophysical studies and fragment-based targeting." Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708479.
Audonnet, Laure. "Caractérisation fonctionnelle de JMJ24, une déméthylase d’histone de la famille JUMONJI, chez Arabidopsis thaliana." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA112033/document.
Numerous studies over the last decade have reported the characterization of the JUMONJI (JMJ) proteins, showing their critical importance in regulating genes and organism’s development. These proteins are able to demethylate a subset of histone tail residues and were clustered into distinct groups using a phylogenetic analysis based on their catalytic domain conservation. Furthermore, modification of one to three specific residues has been attributed to each JMJ group. Within the KDM3 subfamily, of which target is the H3K9 residue, only one member, IBM1, was first characterized in Arabidopsis. In this report, we showed that the mutation of JMJ24, another member of this subfamily, resulted in an increase of the root length, cotyledon and floral organ size, suggesting that JMJ24 functions is needed at different developmental stage. In addition, the analysis of the tissue-specific expression of JMJ24 indicated that the gene is expressed within the phloem of all organs, correlating with the pleiotropic effect of the gene mutation. Last, our data also suggested that JMJ24 interacts with other JMJ protein like JMJ14 and IBM1, but also with the DCL proteins knowing to be involved in genes and transposable elements regulation
Sklias, Athéna. "Epigenetic regulation by estrogen receptor in breast cancer cells." Thesis, Lyon, 2019. http://www.theses.fr/2019LYSE1149/document.
Previous epidemiological and experimental studies have strongly implicated estrogens in breast cancer risk and Estrogen Receptor (ER), the transcription factor to which estrogen binds, is considered as the major molecular driver of around 70% breast cancers. The importance of the deregulated estrogen signalling is further highlighted by increasing evidence that current chemopreventive and therapeutic strategies that target hormonally responsive breast cancers frequently result in the development of resistance to anti-estrogens and metastatic progression, highlighting the need for understanding the molecular underlying mechanisms. While until recently, ER was believed to act as a stand-alone transcription factor, which can directly bind its motifs in DNA, it is now accepted that ER activity is a complex and dynamic process that requires highly concerted actions of a dozen transcriptional cofactors and various chromatin regulators at DNA. Recent studies focused on characterising ER-associated cofactors and their role in opening the chromatin provided a remarkable insight into transcriptional regulation mediated by ER. However DNA methylation and histone acetylation are poorly understood in the context of ER’s dynamic binding. In this thesis, I combined a cell culture protocol adapted for studying estradiol (E2) deprivation and re-stimulation in stricto sensu in ER-positive breast cancer cells with the latest methylation array, that allowed a genome-wide interrogation of DNA methylation (including a comprehensive panel of enhancers). I further investigated histone acetylation (ChIP-seq) and transcriptome (RNA-seq) after E2 deprivation and re-stimulation to better characterise the ability of ER to coordinate gene regulation. I found that E2 deprivation and re-stimulation result in time-dependent DNA methylation changes and in histone acetylation across diverse genomic regions, many of which overlap with enhancers. Further enrichment analysis of transcription factor (TF) binding and motif occurrence highlights the importance of ER tethering mainly through two partner TF families, AP-1 and FOX, in the proximity of enhancers that are differentially methylated and acetylated. This is the first study that comprehensively characterized DNA methylation at enhancers in response to inhibition and activation of ER signalling. The transcriptome and genome occupancy data further reinforced the notion that ER activity may orchestrate a broad transcriptional programme through regulating a limited panel of critical enhancers. Finally, the E2 re-stimulation experiments revealed that although the majority of the observed epigenetic changes induced by E2 deprivation could be largely reversed when the cells were re-stimulated we show that DNA hypermethylation and H3K27 acetylation at enhancers as well as several gene expression changes are selectively retained. The partial reversibility can be interpreted as a sign of treatment efficiency but also as a mechanism by which ER activity may contribute to endocrine resistance. This study provides entirely new information that constitutes a major advance in our understanding of the events by which ER and its cofactors mediate changes in DNA methylation and chromatin states at enhancers. These findings should open new avenues for studying role of the deregulated estrogen signalling in the mechanism underlying the “roots” of endocrine resistance that commonly develops in response to anti-estrogen therapy
Battisti, Valentine. "Rôle d'histones methyltransférases spécifiques de H3K9 dans l'équilibre prolifération et différenciation cellulaire." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA11T092/document.
In eukaryotes, gene expression partly relies on chromatin compaction degree. Chromatin status is controlled by epigenetic marks, such as histones (chromatin structural proteins) posttranslational modifications. As an example, histone H3 lysine 9 (H3K9) methylation on gene promoters is mainly associated with transcriptional repression. H3K9 is methylated by several enzymes called lysine methyltransferases (KMTs). The aim of my thesis project was to understand the role of the H3K9 KMTs, G9a, GLP, Suv39h1 and SETDB1 in regulating the balance between proliferation and terminal differentiation. For this purpose, I used skeletal muscle terminal differentiation as model. Upon muscle terminal differentiation, myoblasts exit, in an irreversible way, from the cell cycle and under go differentiation where cells fusion and form myotubes. During this process, cell cycle genes are permanently silenced and muscle specific genes are activated. Thesis introduction is divided into three chapters. The first chapter focuses on chromatin and post-translational modifications. The second chapter describes H3K9 methylation characteristics and the role of the four KMTs that I studied during my thesis project: G9a,GLP, Suv39h1 and SETDB1. In the third chapter, the skeletal muscle terminal differentiation model is described in details. Results section reports my two major studies outcomes and their discussion. The first concerns the antagonistic roles of G9a and GLP regarding the muscle terminal differentiation and the second focuses on the role of SETDB1 during muscle differentiation. Finally, I conclude this manuscript by a plainer discussion followed by long term perspectives and an appendix presents other research articles, in which I collaborated during my PhD
Malik, Athar Naveed. "Genome-Wide Identification and Characterization of Stimulus-Responsive Enhancers in the Nervous System." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:11026.
Leung, Danny Chi Yeu. "Transcriptional silencing of endogenous retroviruses : interplay between histone H3K9 methylation and DNA methylation." Thesis, University of British Columbia, 2011. http://hdl.handle.net/2429/38966.
Hajmirza, Azadeh. "H3K9 trimethylation controls oncogenic signaling and the malignant state in mantle cell lymphoma." Thesis, Université Grenoble Alpes (ComUE), 2017. http://www.theses.fr/2017GREAV084.
Mantle cell lymphoma (MCL) is an aggressive lymphoid cancer characterised by iterative clinical relapses and short survival. MCL displays complex genetics and hallmarks of misregulated expression of lineage specific genes. We have hypothesized that the latter might result from corruption of H3 lysine 9 trimethylation signaling. By screening for H3K9me3 levels across a cohort of 120 MCL cases, we found global reductions in H3K9me3 in 1/3 of cases. H3K9me3 depletion was linked to underexpression / attenuated activity of SUV39H1 and SETDB1 histone methylases, respectively, and to differential expression of key cancer signatures relating to embryonic/hematopoietic stem cell function, B cell differentiation, and DNA damage response. Targeted deep sequencing did not reveal association to mutations in known epigenetic modifiers, indicating a new, previously-unsuspected role for H3K9me3 in MCL pathogenesis. In keeping with this, knockdown of SUV39H1 increased tumour growth in MCL xenografts while SETDB1 depletion induced G1/S arrest coincident to reprogramming to a pre-B cell phenotype. Taken together this identifies convergence of H3K9me3 signaling pathways to essential targets for MCL disease pathogenesis. These are currently under investigation by H3K9me3 ChIP-seq. Survival analyses in the setting of a prospective clinical trial will establish the prognostic impact of H3K9me3 in MCL
Lange, Ulrike Christa [Verfasser], and Roland [Akademischer Betreuer] Schüle. "Characterisation of H3K64 trimethylation as novel heterochromatic mark in the context of DNA methylation and H3K9 trimethylation = Charakterisierung der heterochromatischen Histonmodifikation H3K64 Trimethylierung im Kontext von DNA Methylierung und H3K9 Trimethylierung." Freiburg : Universität, 2012. http://d-nb.info/112346796X/34.
Ee, Ly-Sha. "Regulation of Pluripotency and Differentiation by Chromatin Remodeling Factors." eScholarship@UMMS, 2017. https://escholarship.umassmed.edu/gsbs_diss/921.
Ee, Ly-Sha. "Regulation of Pluripotency and Differentiation by Chromatin Remodeling Factors." eScholarship@UMMS, 2008. http://escholarship.umassmed.edu/gsbs_diss/921.
Dahlberg, Olle. "Gene regulation during development by chromatin and the Super Elongation Complex." Doctoral thesis, Stockholms universitet, Institutionen för molekylär biovetenskap, Wenner-Grens institut, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-103066.
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 1: Manuscript. Paper 3: Manuscript.
Gessaman, Jordan. "Dissection of the Mechanisms Controlling H3K9me3 and DNA Methylation in Neurospora crassa." Thesis, University of Oregon, 2018. http://hdl.handle.net/1794/23129.
Thakrar, Sanjay. "Epigenetic profiling of the developing zebrafish embryo, and technical developments towards cloning zebrafish and isolating pluripotent stem cells." Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/4510.
Cruz, Tapias Paola. "Un mécanisme de trans-méthylation entre les deux principales méthyltransférases de H3K9 SETDB1 et SUV39H1, régule l'établissement de l'hétérochromatine." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC285.
Histone H3 lysine 9 (H3K9) methylation, which is established by the lysine methyltransferases (KMTs) SETDB1, SUV39H1, G9A and GLP, is a central epigenetic mechanism involved in cell fate regulation. In particular, H3K9 methylation is directly involved in heterochromatin formation and gene silencing. Our lab showed that the main H3K9 KMTs (SETDB1, G9A, GLP and SUV39H1) form a functional megacomplex involved in transcriptional silencing, probably via the cooperative establishment of the different H3K9 methylation levels. However, up to now, the regulation of the H3K9 KMT complexes is not fully understood. Interestingly, post-translational modifications (PTMs) have been implicated in the regulation of H3K9 KMT functions. In this, my PhD thesis aimed to decipher how methylation of SETDB1, regulates its activity (complex formation, interaction with partners, recruitment to chromatin), which ultimately could impact on heterochromatin formation, gene expression and cell fate regulation. SETDB1 is crucial during development and cellular differentiation. Moreover, SETDB1 is essential in mouse embryonic stem cells (mESCs) pluripotency and self-renewal, Setbd1 KO is lethal at the peri-implantation stage at 7.5 days postcoitum (dpc). Beside histones, SETDB1 is also able to methylate other proteins (e.g. UBF, ING2, p53). Notably, my current data show that SETDB1 undergoes (auto)methylation on the lysines K1170 and K1178 located inside its catalytic SET domain. SETDB1 and SUV39H1 coordinate the establishment and maintenance of H3K9me3 at constitutive pericentromeric heterochromatin and co-regulate many genomic targets within heterochromatin, including transposable elements, such as long interspersed nuclear elements (LINEs) and endogenous retroviruses (ERVs). Since SUV39H1 is a H3K9 tri-methyltransferase that uses H3K9me1 or H3K9me2 as a primary substrate, SETDB1 could probably provide mono- or di-methylated H3K9. Interestingly, my results point to a model in which SETDB1 auto-methylation paves the path to a subsequent trans-methylation by SUV39H1. This mechanism could regulate not only the SETDB1/SUV39H1 physical interaction (via the SUV39H1 chromodomain), but also cooperation in the establishment and maintenance of both heterochromatin blocks (large domains) and transposable elements (TEs) silencing, at least in ES cells. Thus, we would like to better understand how the crosstalk between these two key H3K9 KMTs, SETDB1 and SUV39H1, occurs in terms of interaction and recruitment to target loci
Bruton, Peter Christopher. "Epigenetic regulation of heterochromatin structure and tumour progression." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/33232.
出口, 勝彰. "マウス生殖細胞におけるH3K9メチル化機構および機能の解析". 京都大学 (Kyoto University), 2013. http://hdl.handle.net/2433/175173.
Audonnet, Laure. "Caractérisation fonctionnelle de JMJ24, une déméthylase d'histone de la famille JUMONJI, chez Arabidopsis thaliana." Phd thesis, Université Paris Sud - Paris XI, 2014. http://tel.archives-ouvertes.fr/tel-00998046.
Irmak, Dilber [Verfasser], David [Gutachter] Vilchez, and Aleksandra [Gutachter] Trifunovic. "Modulation of ATF7IP in Huntington’s disease patient-derived iPSCs prevents neural gene expression changes induced by H3K9 trimethylation / Dilber Irmak ; Gutachter: David Vilchez, Aleksandra Trifunovic." Köln : Universitäts- und Stadtbibliothek Köln, 2018. http://d-nb.info/1188811053/34.
Kessler, Roman 1983. "Molecular and functional characterization of the HP1c complex in Drosophila melanogaster." Doctoral thesis, Universitat Pompeu Fabra, 2014. http://hdl.handle.net/10803/315472.
Al contrario de proteinas HP1 características, la isoforma HP1c de Drosophila melanogaster es una proteína eucromatica. HP1c se encuentra en un complejo con las proteínas “zinc finger” ROW y WOC, que son esenciales para la función de HP1c. En este trabajo, quisimos caracterizar el complejo HP1c en más detalle. Purificamos varios factores nuevos que se unen al complejo. En particular, caracterizamos el receptor de ubiquitina Dsk2 como una unidad principal del complejo HP1c. Además, demostramos que el complejo HP1c se une a TSS de genes que se transcriben activamente y que influye positivamente en su transcripción. El complejo HP1c favorece un estado activo de cromatina en los genes donde se encuentra. Nuestros resultados indican que este mechansimo incluye una regulación de los niveles de H2Bub1 a través de Dsk2
Fang, Pin-Chung, and 方秉中. "The Relationship of Transformational Leadership, Leader-Member Exchange on Job Satisfaction:Taking Perceived Organizational Support as the Intervening Variables." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/h3k9dh.
國立臺北大學
企業管理學系
102
Since talents are important assets of an enterprise, how to enhance job satisfaction to retain talents has become an important issue for business leaders. Previous researchers have found that Transformational Leadership has positive influences on Job Satisfaction. Perceived Organizational Support has positive influences on Job Satisfaction, too. This study investigated the effects of Transformational Leadership and Leader-Member Exchange on Job Satisfaction, and verified if there is mediating effect of Perceived Organizational Support. This study analyzed 200 valid questionnaires on these effects and the findings are as the follows: (1) Transformational Leadership is positively related to Perceived Organizational Support. (2) Leader-Member Exchange is positively related to Perceived Organizational Support. (3) Perceived Organizational Support is positively related to n Job Satisfaction. (4) Transformational Leadership is positively related to Job Satisfaction. (5) Leader-Member Exchange is positively related to Job Satisfaction. (6) Perceived Organizational Support is a mediator between Transformational Leadership and Job Satisfaction. (7) Perceived Organizational Support is a mediator between Leader-Member Exchange and Job Satisfaction. We expect the results of this study can provide a reference on the management practices for enterprises and as the bases for further academic studies.
Peng, Shao-Fu, and 彭少甫. "Integration process and voltage endurance of vertical organic transistor." Thesis, 2016. http://ndltd.ncl.edu.tw/handle/h3k7an.
Dou, Zheng, and 竇. 征. "Mini photo bioreactor array for characterization of interdependence of gene expression of bacterial optogenetic circuits and microbial growth." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/h3kfa2.
國立清華大學
電子工程研究所
106
Light can replace the chemical effector for programming on-demand gene expression in bacteria. Existing tools for optogenetic bacterial circuits remain cumbersome and labor intensive even for simple tasks, such as measuring growth-related gene expression. We present an array of min photobioreactors that monitors the response of optogenetic bacterial circuits to light. The array enables automated, in vivo parallelizable monitoring in real-time and enable the measurement of the host circuit interaction for a synthetic optogenetic circuit, CcaS-CcaR light sensing system in Escherichia coli. Each bioreactor measures the optical density and fluorescence and applies light-source intervention of the gene expression control. The bioreactor array is demonstrated on the CcaS–CcaR light sensing system in Escherichia coli. The interdependence between microbial growth and optogenetic gene expression is confirmed in a growth experiment with three effectors of microbial growth (carbon source, oxygenation, and antibiotic drug concentration). Growth under different carbon sources and oxygenation levels can be explained in the context of resource allocation trade off picture.
Probst, Clemens Kemena. "Glycoprotein-NMB and the microphthalmia-associated transcription factor regulatory circuitry in tuberous sclerosis complex associated tumors." Thesis, 2020. https://hdl.handle.net/2144/41160.
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Ghugari, Rahul. "Histone H3 lysine 56 acetylation and deacetylation pathways as targets for novel antifungal therapies in Candida albicans." Thèse, 2018. http://hdl.handle.net/1866/21180.
Chen, Min-Wei, and 陳民瑋. "H3K9 Histone Methyltransferase G9a Promotes Cancer Cell Invasion and Metastasis." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/23603814540857504865.
國立臺灣大學
毒理學研究所
99
G9a is a mammalian histone methyltransferase that contributes to the epigenetic silencing of tumor suppressor genes. Emerging evidence suggests that G9a is required to maintain the malignant phenotype, but the role of G9a function in mediating tumor metastasis has not been explored. Here, we show that G9a is expressed in aggressive lung cancer cells, and its elevated expression correlates with poor prognosis. RNAi-mediated knockdown of G9a in highly invasive lung cancer cells inhibited cell migration and invasion in vitro and metastasis in vivo. Conversely, ectopic G9a expression in weakly invasive lung cancer cells increased motility and metastasis. Mechanistic investigations suggested that repression of the cell adhesion molecule Ep-CAM mediated the effects of G9a. First, RNAi-mediated knockdown of Ep-CAM partially relieved metastasis suppression imposed by G9a suppression. Second, an inverse correlation between G9a and Ep-CAM expression existed in primary lung cancer. Third, Ep-CAM repression was associated with promoter methylation and an enrichment for dimethylated histone H3K9. G9a knockdown reduced the levels of H3K9 dimethylation and decreased the recruitment of the transcriptional cofactors HP1, DNMT1, and HDAC1 to the Ep-CAM promoter. Our findings establish a functional contribution of G9a overexpression with concomitant dysregulation of epigenetic pathways in lung cancer progression. In addition, G9a may also have functions in cancer cell motility, survival and angiogenic activity. Our results underscore the utility of developing G9a inhibitors as a potentially powerful therapeutic target. We also established the HTS platform for inhibitors against the G9a.
Ting-YunWang and 王婷筠. "Comparison of HDAC and H3K9 methylation between arterial and venous flow for venous endothelial damage." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/dj3666.
Yi-PingHsieh and 謝儀蘋. "Analyze the PIP-SAHA targeting H3K9 acetylation genes by next generation sequencing in oral squamous cell carcinoma." Thesis, 2019. http://ndltd.ncl.edu.tw/handle/9xb87w.
Villeneuve, Valérie. "Homéostasie des histones en réponse au dommage à l’ADN et étude d’inhibiteurs de désacétylases d’importance clinique." Thèse, 2015. http://hdl.handle.net/1866/13028.
The chromatin is a complex structure and its plasticity is essential to complete different fundamental cellular processes such as DNA replication, transcription and repair. Furthermore, chromatin malfunction is often associated with cancer emergence. The focus of this thesis will be on the function and regulation of histones, as they are essential components of nucleosomes and they ensure proper chromatin formation. Chapter II of this thesis focuses on the transcriptional repression of histone genes by the HIR (HIstone gene Repressor) complex in response to DNA damage in Saccharomyces cerevisiae. When DNA damage occurs in early S phase, the DNA damage checkpoint kinases Mec1, Tel1 and Rad53 block late origins of replication to limit potentially mutagenic or cytotoxic collisions between DNA polymerases and remaining DNA lesions. When the total DNA synthesis rate drops suddenly in S- phase, following the checkpoint control activation, accumulation of newly synthesized histones becomes detrimental for the cells because free histones bind non-specifically to nucleic acids. One mechanism that contributes to a reduction in free histones at this time is the repression of histone gene transcription; however, the molecular basis of this repression was not known. Our study on histone gene repression in response to genotoxic agents allowed us to identify the checkpoint kinases as major players in the repression of histone genes. Before initiating this project, it was known that the HIR complex is required to repress histone genes in G1 and G2/M phases and during DNA damage. Nonetheless, HIR complex regulation was not well characterized. We demonstrated by mass spectrometry (MS) analyses that Rad53 regulates the HIR complex by directly phosphorylating one of its subunits, Hpc2, at many residues in vivo and in vitro. Hpc2 phosphorylation is essential to recruit the RSC complex (Remodels the Structure of Chromatin) to histone gene promoters where its presence correlates with histone gene repression. Moreover, we uncovered a novel mechanism for the HIR complex regulation during a normal cell cycle progression and in response to genotoxic agents. Indeed, during a normal cell cycle, the Hpc2 protein is very unstable at the G1/S transition to allow histone gene transcription and production of a pool of newly synthesized histones just before DNA replication initiation. These results suggest that Hpc2 is a key player in the regulation of HIR complex activity and can repress histone gene expression both during a normal cell cycle and in response to DNA damage. In order to pursue our study on histone regulation, chapter III of this thesis covers histone acetylation induced by histone deacetylase inhibitors (HDACi) in normal and cancer cells. Histone deacetylases (HDACs) are enzymes that remove acetyl groups from lysine residues on histones, condensing the chromatin and effectively repressing local transcription. Several types of cancers are characterized by epigenetic abnormalities and HDACs contribute to oncogenesis by aberrant fusion with oncogenic protein complexes. The disruptions often lead to an abnormal silent state of tumour suppressors. HDACs are then targets of interest in cancer treatment caused by those fusion proteins. Our study of the effects of two clinically relevant HDAC inhibitors, vorinostat (SAHA) and entinostat (MS-275) on acetylation of histones demonstrated an obvious increase of histones H3 and H4 acetylation, unlike histones H2A and H2B in both normal and cancer cells. Unexpectedly, our MS quantification of histone acetylation revealed that the stoichiometry of histone H3 lysine 56 acetylation (H3K56Ac) was only 0.03% and, surprisingly, this stoichiometry did not increase upon HDACi treatments. Several reported studies in the literature of H3K56Ac in humans are irreconcilable. Furthermore, H3K56Ac was considered as a potential biomarker in diagnosis and prognosis in many cancer types. Therefore we focussed on antibody specificity and determined that the majority of antibodies used in the literature recognize other acetylation sites in histone H3, especially H3K9Ac whose stoichiometry of acetylation in vivo is much higher than H3K56Ac. Additionally, chapter IV is a follow-up of our study on histone acetylation and consists of a special report describing the function of H3K56Ac in yeast and human and also contains an evaluation of a supposedly specific H3K56Ac antibody as a diagnostic tool in human cancers.
Koch, Carmen. "Molekulare und funktionelle Analyse von Windei (CG12340) als Bindungspartner der Histonmethyltransferase Eggless während der Oogenese von Drosophila." Doctoral thesis, 2009. http://hdl.handle.net/11858/00-1735-0000-0006-AD30-D.
Simoneau, Antoine. "Le rôle de la structure de la chromatine naissante dans la réponse au stress réplicatif." Thèse, 2017. http://hdl.handle.net/1866/20234.
Delgoshaie, Neda. "Study of histone H3 lysine 56 deacetylation in saccharomyces cerevisiae." Thèse, 2013. http://hdl.handle.net/1866/10224.