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Demyanenko, Svetlana, and Svetlana Sharifulina. "The Role of Post-Translational Acetylation and Deacetylation of Signaling Proteins and Transcription Factors after Cerebral Ischemia: Facts and Hypotheses." International Journal of Molecular Sciences 22, no. 15 (July 26, 2021): 7947. http://dx.doi.org/10.3390/ijms22157947.
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Histone deacetylase (HDAC) and histone acetyltransferase (HAT) regulate transcription and the most important functions of cells by acetylating/deacetylating histones and non-histone proteins. These proteins are involved in cell survival and death, replication, DNA repair, the cell cycle, and cell responses to stress and aging. HDAC/HAT balance in cells affects gene expression and cell signaling. There are very few studies on the effects of stroke on non-histone protein acetylation/deacetylation in brain cells. HDAC inhibitors have been shown to be effective in protecting the brain from ischemic damage. However, the role of different HDAC isoforms in the survival and death of brain cells after stroke is still controversial. HAT/HDAC activity depends on the acetylation site and the acetylation/deacetylation of the main proteins (c-Myc, E2F1, p53, ERK1/2, Akt) considered in this review, that are involved in the regulation of cell fate decisions. Our review aims to analyze the possible role of the acetylation/deacetylation of transcription factors and signaling proteins involved in the regulation of survival and death in cerebral ischemia.
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Glozak, Michele A., Nilanjan Sengupta, Xiaohong Zhang, and Edward Seto. "Acetylation and deacetylation of non-histone proteins." Gene 363 (December 2005): 15–23. http://dx.doi.org/10.1016/j.gene.2005.09.010.
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Narita, Takeo, Brian T. Weinert, and Chunaram Choudhary. "Functions and mechanisms of non-histone protein acetylation." Nature Reviews Molecular Cell Biology 20, no. 3 (November 22, 2018): 156–74. http://dx.doi.org/10.1038/s41580-018-0081-3.
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Han, Qiuju, Jun Lu, Jizhou Duan, Dongmei Su, Xiaozhe Hou, Fen Li, Xiuli Wang, and Baiqu Huang. "Gcn5- and Elp3-induced histone H3 acetylation regulates hsp70 gene transcription in yeast." Biochemical Journal 409, no. 3 (January 15, 2008): 779–88. http://dx.doi.org/10.1042/bj20070578.
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The purpose of this study was to elucidate the mechanisms by which histone acetylation participates in transcriptional regulation of hsp70 (heat-shock protein 70) genes SSA3 and SSA4 in yeast. Our results indicated that histone acetylation was required for the transcriptional activation of SSA3 and SSA4. The HATs (histone acetyltransferases) Gcn5 (general control non-derepressible 5) and Elp3 (elongation protein 3) modulated hsp70 gene transcription by affecting the acetylation status of histone H3. Although the two HATs possessed overlapping function regarding the acetylation of histone H3, they affected hsp70 gene transcription in different ways. The recruitment of Gcn5 was Swi/Snf-dependent and was required for HSF (heat-shock factor) binding and affected RNAPII (RNA polymerase II) recruitment, whereas Elp3 exerted its roles mainly through affecting RNAPII elongation. These results provide insights into the effects of Gcn5 and Elp3 in hsp70 gene transcription and underscore the importance of histone acetylation for transcriptional initiation and elongation in hsp genes.
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Yan, Li-Ying, Jie Yan, Jie Qiao, Pan-Lin Zhao, and Ping Liu. "Effects of oocyte vitrification on histone modifications." Reproduction, Fertility and Development 22, no. 6 (2010): 920. http://dx.doi.org/10.1071/rd09312.
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Vitrification has been widely used as an assisted reproductive technology in animals and humans, yet the impact of oocyte vitrification and warming on survival and histone modifications has to be evaluated. In the present study, the survival of mouse MII oocytes was assessed after freezing, as were changes in histone 3 lysine 9 (H3K9) dimethylation, histone 4 lysine 5 (H4K5) acetylation and histone 3 lysine 14 (H3K14) acetylation. The results show that, in oocytes subjected to vitrification, H3K9 methylation and H4K5 acetylation were increased. H3K14 acetylation could not be detected in either non-vitrified or vitrified oocytes. Oocytes are very sensitive to changes in H3K9 and H4K5 following vitrification. Both these histone modifications could be useful markers to monitor epigenetic perturbations induced by various experimental vitrification protocols and eventually for optimising the cryopreservation of human oocytes.
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Kuninger, David, James Lundblad, Anthony Semirale, and Peter Rotwein. "A non-isotopic in vitro assay for histone acetylation." Journal of Biotechnology 131, no. 3 (September 2007): 253–60. http://dx.doi.org/10.1016/j.jbiotec.2007.07.498.
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Ito, K. "Impact of post-translational modifications of proteins on the inflammatory process." Biochemical Society Transactions 35, no. 2 (March 20, 2007): 281–83. http://dx.doi.org/10.1042/bst0350281.
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PTM (post-translational modification) is the chemical modification of a protein after its translation. The well-studied PTM is phosphorylation, but, recently, PTMs have been re-focused by extensive studies on histone modifications and the discovery of the ubiquitin system. Histone acetylation is the well-established epigenetic regulator for gene expression. Recent studies show that different patterns of PTMs and cross-talk of individual modifications (acetylation, methylation, phosphorylation) are keys of gene regulation (known as the ‘histone code’). As well as histone, non-histone proteins are also targets of acetylation. For instance, NF-κB (nuclear factor κB), a transcriptional factor, is regulated dynamically by acetylation/deacetylation. Acetylation of NF-κB [RelA (p65)] at Lys310 enhances its transcriptional activity, which is inhibited by SIRT1 deacetylase, type III HDAC (histone deacetylase). We also found that acetylated NF-κB preferentially bound to the IL-8 (interleukin 8) gene promoter, but not to GM-CSF (granulocyte/macrophage colony-stimulating factor), suggesting NF-κB acetylation is involved in selective gene induction as well as an increased level of transcription. A receptor of glucocorticoid, a potent anti-inflammatory agent, is also a target of acetylation. The glucocorticoid receptor is highly acetylated after ligand binding but its deacetylation is necessary for gene repression through binding to NF-κB. As well as acetylation, other PTMs, such as nitration, carbonylation and ubiquitination on transcriptional/nuclear factors, are taking part in the inflammatory process. Cross-talk of individual modifications on proteins deserves further evaluation in the future (as ‘protein code’).
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Wee, G., S. H. Kim, K. P. Kim, S. Yeo, D. B. Koo, S. J. Moon, K. K. Lee, and Y. M. Han. "134INCOMPLETE HISTONE ACETYLATION OF SOMATIC CHROMATIN IN BOVINE OOCYTES." Reproduction, Fertility and Development 16, no. 2 (2004): 189. http://dx.doi.org/10.1071/rdv16n1ab134.
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Histone acetylation as an important regulatory mechanism of chromatin structure preceeding zygotic gene expression in early embryo development. After fertilization, transcriptional activation of the embryo begins during the S/G2 phase of the first cell cycle. However, the precise mechanism underlying activation of zygotic transcription remains to be understood, especially in bovine nuclear transfer (NT) embryos. It is known that acetylation of histone H4 lysine 5 (H4K5) represents hyperacetylation state, which is correlated with gene expression. In this study, the acetylation of H4K5 was observed during pronuclear formation by using immunofluorescence analysis with anti-AcH4K5. Our data were analyzed by the general linear models (GLM) procedure of the SAS. In IVF embryos, acetylation of H4K5 occurred on the paternal chromatin at 8h after fertilization but did not occur on the maternal chromatin until 10h after fertilization. Reconstructed oocytes with deactylated somatic cell nuclei began to show signs of acetylation on chromatin at 3h after fusion. When acetylation intensity was calculated using an image analyzer, IVF embryos presented a higher acetylation signal than NT embryos (P<0.05). To induce hyperacetylation in NT embryos, somatic cells were exposed to trichostatin A (TSA, 1μM for 60h), a specific inhibitor of histone deacetylase (HDAC), prior to NT. Acetylated signals of H4K5 increased significantly in TSA-treated cells as compared with non-treated cells (P<0.05). The reconstructed embryos with TSA-treated cells showed a higher fluorescence intensity than the oocytes with non-treated cells (P<0.05), but weak signals compared to IVF embryos. Thus, the results demonstrated low histone acetylation level of somatic cell nuclei after NT during the zygotic progress. Our findings suggest that developmental failures of NT embryos may be due to incomplete chromatin remodeling of somatic cell nuclei during early embryonic development.
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Bertos, Nicholas R., Audrey H. Wang, and Xiang-Jiao Yang. "Class II histone deacetylases: Structure, function, and regulation." Biochemistry and Cell Biology 79, no. 3 (June 1, 2001): 243–52. http://dx.doi.org/10.1139/o01-032.
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Acetylation of histones, as well as non-histone proteins, plays important roles in regulating various cellular processes. Dynamic control of protein acetylation levels in vivo occurs through the opposing actions of histone acetyltransferases and histone deacetylases (HDACs). In the past few years, distinct classes of HDACs have been identified in mammalian cells. Class I members, such as HDAC1, HDAC2, HDAC3, and HDAC8, are well-known enzymatic transcriptional corepressors homologous to yeast Rpd3. Class II members, including HDAC4, HDAC5, HDAC6, HDAC7, and HDAC9, possess domains similar to the deacetylase domain of yeast Hda1. HDAC4, HDAC5, and HDAC7 function as transcriptional corepressors that interact with the MEF2 transcription factors and the N-CoR, BCoR, and CtBP corepressors. Intriguingly, HDAC4, HDAC5, and probably HDAC7 are regulated through subcellular compartmentalization controlled by site-specific phosphorylation and binding of 14-3-3 proteins; the regulation of these HDACs is thus directly linked to cellular signaling networks. Both HDAC6 and HDAC9 possess unique structural modules, so they may have special biological functions. Comprehension of the structure, function, and regulation of class II deacetylases is important for elucidating how acetylation regulates functions of histones and other proteins in vivo.Key words: histone acetylation, protein acetylation, histone deacetylase, 14-3-3 proteins.
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Narita, Takeo, Brian T. Weinert, and Chunaram Choudhary. "Author Correction: Functions and mechanisms of non-histone protein acetylation." Nature Reviews Molecular Cell Biology 20, no. 8 (July 2, 2019): 508. http://dx.doi.org/10.1038/s41580-019-0156-9.
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Gong, Ping, Yuetong Wang, and Yongkui Jing. "Apoptosis Induction byHistone Deacetylase Inhibitors in Cancer Cells: Role of Ku70." International Journal of Molecular Sciences 20, no. 7 (March 30, 2019): 1601. http://dx.doi.org/10.3390/ijms20071601.
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Histone deacetylases (HDACs) are a group of enzymes that regulate gene transcription by controlling deacetylation of histones and non-histone proteins. Overexpression of HDACs is found in some types of tumors and predicts poor prognosis. Five HDAC inhibitors are approved for the treatment of cutaneous T-cell lymphoma, peripheral T-cell lymphoma, and multiple myeloma. Treatment with HDAC inhibitors regulates gene expression with increased acetylated histones with unconfirmed connection with therapy. Apoptosis is a key mechanism by which HDAC inhibitors selectively kill cancer cells, probably due to acetylation of non-histone proteins. Ku70 is a protein that repairs DNA breaks and stabilizes anti-apoptotic protein c-FLIP and proapoptotic protein Bax, which is regulated by acetylation. HDAC inhibitors induce Ku70 acetylation with repressed c-FLIP and activated Bax in cancer cells. Current studies indicate that Ku70 is a potential target of HDAC inhibitors and plays an important role during the induction of apoptosis.
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Habibian, Justine, and Bradley Ferguson. "The Crosstalk between Acetylation and Phosphorylation: Emerging New Roles for HDAC Inhibitors in the Heart." International Journal of Molecular Sciences 20, no. 1 (December 28, 2018): 102. http://dx.doi.org/10.3390/ijms20010102.
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Approximately five million United States (U.S.) adults are diagnosed with heart failure (HF), with eight million U.S. adults projected to suffer from HF by 2030. With five-year mortality rates following HF diagnosis approximating 50%, novel therapeutic treatments are needed for HF patients. Pre-clinical animal models of HF have highlighted histone deacetylase (HDAC) inhibitors as efficacious therapeutics that can stop and potentially reverse cardiac remodeling and dysfunction linked with HF development. HDACs remove acetyl groups from nucleosomal histones, altering DNA-histone protein electrostatic interactions in the regulation of gene expression. However, HDACs also remove acetyl groups from non-histone proteins in various tissues. Changes in histone and non-histone protein acetylation plays a key role in protein structure and function that can alter other post translational modifications (PTMs), including protein phosphorylation. Protein phosphorylation is a well described PTM that is important for cardiac signal transduction, protein activity and gene expression, yet the functional role for acetylation-phosphorylation cross-talk in the myocardium remains less clear. This review will focus on the regulation and function for acetylation-phosphorylation cross-talk in the heart, with a focus on the role for HDACs and HDAC inhibitors as regulators of acetyl-phosphorylation cross-talk in the control of cardiac function.
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Zakarya, Razia, Yik L. Chan, Sandra Rutting, Karosham Reddy, Jack Bozier, Roy R. Woldhuis, Dikaia Xenaki, et al. "BET proteins are associated with the induction of small airway fibrosis in COPD." Thorax 76, no. 7 (January 27, 2021): 647–55. http://dx.doi.org/10.1136/thoraxjnl-2020-215092.
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RationaleIn COPD, small airway fibrosis occurs due to increased extracellular matrix (ECM) deposition in and around the airway smooth muscle (ASM) layer. Studies of immune cells and peripheral lung tissue have shown that epigenetic changes occur in COPD but it is unknown whether airway mesenchymal cells are reprogrammed.ObjectivesDetermine if COPD ASM cells have a unique epigenetic response to profibrotic cytokine transforming growth factor β1 (TGF-β1).MethodsPrimary human ASM cells from COPD and non-COPD smoking patients were stimulated with TGF-β1. Gene array analysis performed to identify differences in ECM expression. Airway accumulation of collagen 15α1 and tenascin-C proteins was assessed. Aforementioned ASM cells were stimulated with TGF-β1 ± epigenetic inhibitors with qPCR quantification of COL15A1 and TNC. Global histone acetyltransferase (HAT) and histone deacetylase (HDAC) activity were assessed. chromatin immunoprecipitation (ChIP)-qPCR for histone H3 and H4 acetylation at COL15A1 and TNC promoters was carried out. Effects of bromoterminal and extraterminal domain (BET) inhibitor JQ1(+) on expression and acetylation of ECM target genes were assessed.Measurements and main resultsCOPD ASM show significantly higher COL15A1 and TNC expression in vitro and the same trend for higher levels of collagen 15α1 and tenascin-c deposited in COPD airways in vivo. Epigenetic screening indicated differential response to HDAC inhibition. ChIP-qPCR revealed histone H4 acetylation at COL15A1 and TNC promoters in COPD ASM only. ChIP-qPCR found JQ1(+) pretreatment significantly abrogated TGF-β1 induced histone H4 acetylation at COL15A1 and TNC.ConclusionsBET protein binding to acetylated histones is important in TGF-β1 induced expression of COL15A1 and TNC and maintenance of TGF-β1 induced histone H4 acetylation in cell progeny.
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Iancu-Rubin, Camelia, Faye Feller, David Gajzer, John Mascarenhas, and Ronald Hoffman. "Targeting Non-Histone Protein Acetylation Impairs Platelet Production During Normal Megakaryocytopoiesis." Blood 116, no. 21 (November 19, 2010): 2610. http://dx.doi.org/10.1182/blood.v116.21.2610.2610.
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Abstract Abstract 2610 Megakaryocytopoiesis consists of a succession of events in which MK progenitors initially proliferate and acquire lineage-specific markers, followed by polyploidization and cytoplasmic maturation. MK maturation culminates in the formation of cytoplasmic extensions (i.e. proplatelets) that leads to platelet shedding into the circulation. Panobinostat (LBH589) is a histone deacetylase inhibitor that has antiproliferative and cytotoxic effects on several types of cancer cells including blood cells from patients with hematological malignancies. One of the major adverse events associated with LBH589 treatment is thrombocytopenia. In this study, we hypothesize that the effects of LBH589 on thrombopoiesis might occur by targeting acetylation of histone and/or non-histone proteins resulting in defective platelet production. To test this hypothesis we investigated the effects of LBH589 on megakaryocytopoiesis in MK cell lines (i.e. HEL JAK2V617F positive cells) and in primary human MK. First, we tested the effects of LBH589 on the ability of human CD34+ cells to generate MK colony forming units (CFU-MKs). Neither CFU-MK or CFU-MIX derived colony formation was reduced in the presence of LBH589. To evaluate the effects of LBH589 on parameters of MK maturation, MK were generated in vitro from peripheral blood-derived CD34+ cells by employing an expansion culture system containing SCF and TPO for 6 days followed by 8 additional days incubation in the presence of TPO. These studies were pursued in the presence or absence of LBH589. Treatment with LBH589 did not significantly influence the number of CD61+ MK (i.e. control = 55.8%; 2.5nM LBH589 = 45.2%, p value=0.109; 5nM LBH589=38.5%, p value=0.095, of viable 7-AAD−/CD61+ cells) or the degree of polyploidization (i.e. control = 17.4%; 2.5nM LBH589 = 14.4%86.7, p value=0.157; 5nM LBH 589=12.8%, p value=0.116, cells with >4N DNA content). Culture-derived platelets were analyzed phenotypically and quantitated by means of dual labeling with anti-CD41 antibodies and with thiazole orange (TO) in order to identify new reticulated platelets. The percentage of CD41+/TO+ platelets derived from MK generated in the presence of LBH589 was significantly reduced (i.e. 2.5nM LBH589=11%, p value 0.046 and 5nM LBH589=9%, p value=0.011, CD41+/TO+ cells) as compared with MK generated in the absence of LBH589 (18.5% CD41+/TO+ cells). These findings were consistent with the observation of significant numbers of proplatelet-bearing MKs in control cultures but not in LBH 589-treated cultures. Collectively, these data suggest that LBH589 impairs platelet production while having a minimal effect on MK commitment, cytoplasmic maturation or polyploidization. To better understand the mechanisms responsible for such effects on thrombopoiesis, RNA extracted from control MK and from MK treated in vitro with LBH589 was analyzed by real time quantitative PCR to evaluate GATA-1 and NF-E2 expression. GATA-1 and NF-E2 mRNA levels were unchanged after treatment with LBH589. We found, however, that LBH589 induced a 4.8 to 7.5-fold increase in histone H3 acetylation. These data suggest that the negative impact of LBH589 on MK maturation was not mediated by its effects on chromatin but rather was possibly due to its effects on acetylation of nonhistone proteins. We demonstrated that LBH589 treatment increased acetylation of tubulin, a non-histone cytoplasmic protein that is a component of the microtubule (MT) cytoskeleton. The later stages of MK maturation are highly dependent on MT which represent the structural scaffold for proplatelet extension and enables the transport of cytoplasmic organelles into nascent platelets. The changes in the acetylation status of tubulin are critical for proper MT function and are mediated by HDAC6 which we found by Western blot analysis to be inhibited by LBH589 treatment. Based on these findings we suggest that LBH589-induced changes in tubulin acetylation result in aberrant MT function which in turn, leads to defective proplatelet and platelet formation. These nonhistone protein modifications might serve as a drug target for the development of novel agents (LBH589) to treat patients with extreme thrombocytosis due to underlying myeloproliferative neoplasms. Disclosures: Iancu-Rubin: Novartis: Research Funding. Hoffman:Novartis: Research Funding.
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Spange, Stephanie, Tobias Wagner, Thorsten Heinzel, and Oliver H. Krämer. "Acetylation of non-histone proteins modulates cellular signalling at multiple levels." International Journal of Biochemistry & Cell Biology 41, no. 1 (January 2009): 185–98. http://dx.doi.org/10.1016/j.biocel.2008.08.027.
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Barlesi, F., G. Giaccone, M. I. Gallegos-Ruiz, A. Loundou, S. W. Span, P. Lefesvre, F. A. Kruyt, and J. Rodriguez. "Global histone modifications predict prognosis of resected non-small cell lung cancer patients." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 7662. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.7662.
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7662 Background: Epigenetic modifications, such as methylation and/or acetylation of histones, may contribute to the development and progression of cancer. We investigated whether histone modifications influence prognosis of non-small cell lung cancer (NSCLC). Methods: We used immunohistochemistry to assess histone 3 lysine 4 dimethylation (H3K4diMe), and acetylation of histone 2A lysine 5 (H2AK5Ac), histone 2B lysine 12 (H2BK12Ac), histone 3 lysine 9 (H3K9Ac), and histone 4 lysine 8 (H4K8Ac), in resected tumor samples of 138 NSCLC patients. In addition, the genotype of a tandem repeat polymorphism in the histone 3 methyltransferase SMYD3 gene was determined using PCR and capillary electrophoresis. Data were analyzed using a recursive partitioning analysis (RPA). Results: The overall median expression of H3K4diMe, H2AK5Ac, H2BK12Ac, H3K9Ac, and H4K8Ac were 75, 10, 0, 25, and 80%, respectively. The RPA classified the patients into seven distinct prognostic groups based on TNM stage (first node), histology (second node) and histone modifications (third node). H3K4diMe (< or =85% tumor cells), H3K9Ac (< or =68% tumor cells) and H2AKAc (< or =5% tumor cells) were retained by RPA. The SMYD3 genotype was not retained by RPA. The seven groups were associated with significantly different disease- free (p<0.0001) and overall survival (p<0.0001). Interestingly, the four groups determined by stage I patients (below the first node) displayed dramatic differences in survival (median from 10 months in adenocarcinoma, H3K9Ac=68%, to 147 months in non-adenocarcinoma, H3K4diMe=85%). Conclusions: The prognostic influence of global histone modifications is greater in early stage NSCLC and it may help in the selection of early stage NSCLC patients for adjuvant treatment and provides a rationale for the use of combination of standard chemotherapy with drugs interacting with histone modifications such as histone deacetylases (HDAC) inhibitors. No significant financial relationships to disclose.
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Abbring, Wolf, Ayechu-Muruzabal, Diks, Alhamdan, Harb, Renz, et al. "Raw Cow’s Milk Reduces Allergic Symptoms in a Murine Model for Food Allergy—A Potential Role For Epigenetic Modifications." Nutrients 11, no. 8 (July 25, 2019): 1721. http://dx.doi.org/10.3390/nu11081721.
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Epidemiological studies identified raw cow’s milk consumption as an important environmental exposure that prevents allergic diseases. In the present study, we investigated whether raw cow’s milk has the capacity to induce tolerance to an unrelated, non-milk, food allergen. Histone acetylation of T cell genes was investigated to assess potential epigenetic regulation. Female C3H/HeOuJ mice were sensitized and challenged to ovalbumin. Prior to sensitization, the mice were treated with raw milk, processed milk, or phosphate-buffered saline for eight days. Allergic symptoms were assessed after challenge and histone modifications in T cell-related genes of splenocyte-derived CD4+ T cells and the mesenteric lymph nodes were analyzed after milk exposure and after challenge. Unlike processed milk, raw milk decreased allergic symptoms. After raw milk exposure, histone acetylation of Th1-, Th2-, and regulatory T cell-related genes of splenocyte-derived CD4+ T cells was higher than after processed milk exposure. After allergy induction, this general immune stimulation was resolved and histone acetylation of Th2 genes was lower when compared to processed milk. Raw milk reduces allergic symptoms to an unrelated, non-milk, food allergen in a murine model for food allergy. The activation of T cell-related genes could be responsible for the observed tolerance induction, which suggested that epigenetic modifications contribute to the allergy-protective effect of raw milk.
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Shimazu, Tadahiro, Sueharu Horinouchi, and Minoru Yoshida. "Multiple Histone Deacetylases and the CREB-binding Protein Regulate Pre-mRNA 3′-End Processing." Journal of Biological Chemistry 282, no. 7 (December 17, 2006): 4470–78. http://dx.doi.org/10.1074/jbc.m609745200.
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Trichostatin A (TSA), a specific inhibitor of histone deacetylases (HDACs), induces acetylation of various non-histone proteins such as p53 and α-tubulin. We purified several acetylated proteins by the affinity to an anti-acetylated lysine (AcLys) antibody from cells treated with TSA and identified them by mass spectrometry. Here we report on acetylation of CFIm25, a component of mammalian cleavage factor Im (CF Im), and poly(A) polymerase (PAP), a polyadenylating enzyme for the pre-mRNA 3′-end. The residues acetylated in these proteins were mapped onto the regions required for interaction with each other. Whereas CBP acetylated these proteins, HDAC1, HDAC3, HDAC10, SIRT1, and SIRT2 were involved in in vivo deacetylation. Acetylation of the CFIm25 occurred depending on the cleavage factor complex formation. Importantly, the interaction between PAP and CF Im complex was decreased by acetylation. We also demonstrated that acetylation of PAP inhibited the nuclear localization of PAP by inhibiting the binding to the importin α/β complex. These results suggest that CBP and HDACs regulate the 3′-end processing machinery and modulate the localization of PAP through the acetylation and deacetylation cycle.
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Sobel, R. E., R. G. Cook, and C. D. Allis. "Non-random acetylation of histone H4 by a cytoplasmic histone acetyltransferase as determined by novel methodology." Journal of Biological Chemistry 269, no. 28 (July 1994): 18576–82. http://dx.doi.org/10.1016/s0021-9258(17)32348-7.
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Gan, Lei, Zhenzhen Wei, Zuoren Yang, Fuguang Li, and Zhi Wang. "Updated Mechanisms of GCN5—The Monkey King of the Plant Kingdom in Plant Development and Resistance to Abiotic Stresses." Cells 10, no. 5 (April 22, 2021): 979. http://dx.doi.org/10.3390/cells10050979.
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Histone modifications are the main epigenetic mechanisms that regulate gene expression, chromatin structure, and plant development, among which histone acetylation is one of the most important and studied epigenetic modifications. Histone acetylation is believed to enhance DNA access and promote transcription. GENERAL CONTROL NON-REPRESSIBLE 5 (GCN5), a well-known enzymatic protein responsible for the lysine acetylation of histone H3 and H4, is a universal and crucial histone acetyltransferase involved in gene transcription and plant development. Many studies have found that GCN5 plays important roles in the different development stages of Arabidopsis. In terms of exogenous stress conditions, GCN5 is also involved in the responses to heat stress, cold stress, and nutrient element deficiency by regulating the related gene expression to maintain the homeostasis of some key metabolites (e.g., cellulose) or ions (e.g., phosphate, iron); in addition, GCN5 is involved in the phytohormone pathways such as ethylene, auxin, and salicylic acid to play various roles during the plant lifecycle. Some of the pathways involved by GCN5 also interwind to regulate specific physiological processes or developmental stages. Here, interactions between various developmental events and stress-resistant pathways mediated by GCN5 are comprehensively addressed and the underlying mechanisms are discussed in the plant. Studies with some interacting factors such as ADA2b provided valuable information for the complicated histone acetylation mechanisms. We also suggest the future focuses for GCN5 functions and mechanisms such as functions in seed development/germination stages, exploration of novel interaction factors, identification of more protein substrates, and application of advanced biotechnology-CRISPR in crop genetic improvement, which would be helpful for the complete illumination of roles and mechanisms of GCN5.
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Scott, Iain. "Regulation of cellular homoeostasis by reversible lysine acetylation." Essays in Biochemistry 52 (May 25, 2012): 13–22. http://dx.doi.org/10.1042/bse0520013.
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Acetylation, through the post-transcriptional modification of histones, is a well-established regulator of gene transcription. More recent research has also identified an important role for acetylation in the regulation of non-histone proteins, both inside and outside the nucleus. As a fast (and reversible) post-translational process, acetylation allows cells to rapidly alter the function of existing proteins, making it ideally suited to biological programmes that require an immediate response to changing conditions. Using metabolic programmes as an example, the present chapter looks at how reversible acetylation can be used to regulate important enzymes in an ever-changing cellular environment.
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Hayakawa, Fumihiko, Issay Kitabayashi, Pier P. Pandolfi, and Tomoki Naoe. "Acetylation of PML Plays a Key Role in Histone Deacetylase Inhibitor-Mediated Apoptosis through Enhanced PML Sumoylation." Blood 110, no. 11 (November 16, 2007): 4164. http://dx.doi.org/10.1182/blood.v110.11.4164.4164.
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Abstract The promyelocytic leukemia (PML) protein is a potent tumor suppressor and proapoptotic factor, and is functionally regulated by posttranslational modification such as phosphorylation, sumoylation, and ubiquitination. Histone deacetylase (HDAC) inhibitors are a promising class of targeted anticancer agents and induce apoptosis to cancer cells. In addition to their effects on histones, HDAC inhibitors increase the acetylation level of several non-histone proteins such as transcription factors, which are important for their effects to cancer cells. However, the mechanism of HDAC inhibitor-induced apoptocis is largely unknown. We report here a novel posttranscriptional modification, acetylation, of PML. By the screening using antibody array, we identified PML as a new acetylation target of Trichostatin A (TSA), a HDAC inhibitor. PML acetylation was enhanced by coexpression of p300 or treatment with TSA. We also showed that increased PML acetylation was associated with increased sumoylation of PML in vitro and in vivo. PML involvement in TSA-induced apoptosis was demonstrated by PML knocking down in Hela cells or PML overexpression in PML−/− MEF cells. Furthermore, PML with acetylation-defective mutation showed disability to mediate the apoptosis, suggesting the importance of PML acetylation for it. Our work provides new insights into the PML regulation by posttranslational modification, and new information about the therapeutic mechanism of HDAC inhibitors.
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Iaconelli, Jonathan, Lucius Xuan, and Rakesh Karmacharya. "HDAC6 Modulates Signaling Pathways Relevant to Synaptic Biology and Neuronal Differentiation in Human Stem-Cell-Derived Neurons." International Journal of Molecular Sciences 20, no. 7 (March 31, 2019): 1605. http://dx.doi.org/10.3390/ijms20071605.
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Recent studies show that histone deacetylase 6 (HDAC6) has important roles in the human brain, especially in the context of a number of nervous system disorders. Animal models of neurodevelopmental, neurodegenerative, and neuropsychiatric disorders show that HDAC6 modulates important biological processes relevant to disease biology. Pan-selective histone deacetylase (HDAC) inhibitors had been studied in animal behavioral assays and shown to induce synaptogenesis in rodent neuronal cultures. While most studies of HDACs in the nervous system have focused on class I HDACs located in the nucleus (e.g., HDACs 1,2,3), recent findings in rodent models suggest that the cytoplasmic class IIb HDAC, HDAC6, plays an important role in regulating mood-related behaviors. Human studies suggest a significant role for synaptic dysfunction in the prefrontal cortex (PFC) and hippocampus in depression. Studies of HDAC inhibitors (HDACi) in human neuronal cells show that HDAC6 inhibitors (HDAC6i) increase the acetylation of specific lysine residues in proteins involved in synaptogenesis. This has led to the hypothesis that HDAC6i may modulate synaptic biology not through effects on the acetylation of histones, but by regulating acetylation of non-histone proteins.
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Stewart, M. David, John Sommerville, and Jiemin Wong. "Dynamic Regulation of Histone Modifications in Xenopus Oocytes through Histone Exchange." Molecular and Cellular Biology 26, no. 18 (September 15, 2006): 6890–901. http://dx.doi.org/10.1128/mcb.00948-06.
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ABSTRACT Histone H3 lysine 9 (H3K9) methylation has broad roles in transcriptional repression, gene silencing, maintenance of heterochromatin, and epigenetic inheritance of heterochromatin. Using Xenopus laevis oocytes, we have previously shown that targeting G9a, an H3K9 histone methyltransferase, to chromatin increases H3K9 methylation and consequently represses transcription. Here we report that treatment with trichostatin A induces histone acetylation and is sufficient to activate transcription repressed by G9a, and this activation is accompanied by a reduction in dimethyl H3K9 (H3K9me2). We tested the possibility that the reduction in H3K9me2 was due to the replacement of methylated H3 with unmethylated H3.3. Surprisingly, we found that both free H3 and H3.3 are continually exchanged with chromatin-associated histones. This dynamic exchange of chromatin-associated H3 with free H3/H3.3 was not affected by alterations in transcriptional activity, elongation, acetylation, H3K9 methylation, or DNA replication. In support of this continual histone exchange model, we show that maintenance of H3K9 methylation at a specific site requires the continual presence of an H3K9 histone methyltransferase. Upon dissociation of the methyltransferase, H3K9 methylation decreases. Taken together, our data suggest that chromatin-associated and non-chromatin-associated histones are continually exchanged in the Xenopus oocyte, creating a highly dynamic chromatin environment.
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Zakhartchenko, V., F. Yang, R. Hao, and E. Wolf. "102 RABBIT CLONING: HISTONE ACETYLATION STATUS OF DONOR CELLS AND CLONED EMBRYOS." Reproduction, Fertility and Development 19, no. 1 (2007): 168. http://dx.doi.org/10.1071/rdv19n1ab102.
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Epigenetic status of the genome of a donor nucleus is likely to be associated with the developmental potential of cloned embryos produced by somatic cell nuclear transfer (SCNT). Prevention of epigenetic errors by manipulation of the epigenetic status of donor cells is expected to result in improvement of cloning efficiency. In this study, we transferred cultured rabbit cumulus cells (RCC) and fetal fibroblasts (RFF) from genetically marked rabbits (Ali/Bas) into metaphase II (MII) oocytes and analyzed the levels of histone H3K9 acetylation in donor cells and cloned embryos. We also assessed the correlation between the histone acetylation status of donor cells and cloned embryos and their developmental potential. To test whether alteration of the histone acetylation status affects development of cloned embryos, we treated donor cells with sodium butyrate (NaBu), a histone deacetylase inhibitor. Further, we tried to improve cloning efficiency by chimeric complementation of cloned embryos with one or two blastomeres from in vitro-fertilized or parthenogenetic embryos. Histone acetylation in donor cells and cloned embryos was detected by anti-acH3K9 antibody using Western immunoblot analysis or immunochemistry, respectively. Data were analyzed by chi-square (developmental rates) or Student-Newman-Keuls (histone acetylation) test. The levels of acetylated histone H3K9 were higher in RCCs than in RFFs (P < 0.05). Although the type of donor cells did not affect development to blastocyst, after transfer into recipients, RCC-cloned embryos induced a higher initial pregnancy rate as compared to RFF-cloned embryos (40% vs. 20%; P < 0.05). However, almost all pregnancies with either type of cloned embryos were lost by the middle of gestation and only one fully developed; a live RCC-derived rabbit was obtained. Treatment of RFFs with NaBu significantly (P < 0.05) increased the level of histone H3K9/14 acetylation and the proportion of nuclear transfer embryos developing to blastocyst (49% vs. 33% with non-treated RFF; P < 0.05). The distribution of signals for acH3K9 in either group of cloned embryos did not resemble that in in vivo-fertilized embryos, suggesting that reprogramming of this epigenetic mark is aberrant in cloned rabbit embryos and cannot be corrected by treatment of donor cells with NaBu. Aggregation of embryos cloned from NaBu-treated RFFs with blastomeres from in vivo-derived embryos improved development to blastocyst, but no cloned offspring were obtained. Two live cloned rabbits were produced from this donor cell type only after aggregation of cloned embryos with a parthenogenetic blastomere. Our study demonstrates that the levels of histone acetylation in donor cells and cloned embryos correlate with their developmental potential and can be a useful epigenetic mark to predict efficiency of SCNT rabbits. This work was supported by the Bayerische Forschungsstiftung and by Therapeutic Human Polyclonals, Inc.
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Elmallah, Mohammed I. Y., and Olivier Micheau. "Epigenetic Regulation of TRAIL Signaling: Implication for Cancer Therapy." Cancers 11, no. 6 (June 19, 2019): 850. http://dx.doi.org/10.3390/cancers11060850.
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One of the main characteristics of carcinogenesis relies on genetic alterations in DNA and epigenetic changes in histone and non-histone proteins. At the chromatin level, gene expression is tightly controlled by DNA methyl transferases, histone acetyltransferases (HATs), histone deacetylases (HDACs), and acetyl-binding proteins. In particular, the expression level and function of several tumor suppressor genes, or oncogenes such as c-Myc, p53 or TRAIL, have been found to be regulated by acetylation. For example, HATs are a group of enzymes, which are responsible for the acetylation of histone proteins, resulting in chromatin relaxation and transcriptional activation, whereas HDACs by deacetylating histones lead to chromatin compaction and the subsequent transcriptional repression of tumor suppressor genes. Direct acetylation of suppressor genes or oncogenes can affect their stability or function. Histone deacetylase inhibitors (HDACi) have thus been developed as a promising therapeutic target in oncology. While these inhibitors display anticancer properties in preclinical models, and despite the fact that some of them have been approved by the FDA, HDACi still have limited therapeutic efficacy in clinical terms. Nonetheless, combined with a wide range of structurally and functionally diverse chemical compounds or immune therapies, HDACi have been reported to work in synergy to induce tumor regression. In this review, the role of HDACs in cancer etiology and recent advances in the development of HDACi will be presented and put into perspective as potential drugs synergizing with TRAIL’s pro-apoptotic potential.
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Martínez-López, W., and M. V. Di Tomaso. "Chromatin remodelling and chromosome damage distribution." Human & Experimental Toxicology 25, no. 9 (September 2006): 539–45. http://dx.doi.org/10.1191/0960327106het650oa.
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Histone acetylation/deacetylation constitute the most relevant chromatin remodelling mechanism to control DNA access to nuclear machinery as well as to mutagenic agents. Thus, these epigenetics mechanisms could be involved in processing DNA lesions into chromosomal aberrations. Although radiation-induced DNA lesions are believed to occur randomly, in most cases chromosome breakpoints appear distributed in a non-random manner. In order to study the distribution of chromosome damage induced by clastogenic agents in relation to chromosome histone acetylation patterns, an experimental model based on treating Chinese hamster cells with endonucleases and ionizing radiations as well as immunolabelling metaphase chromosomes with antibodies to acetylated histone H4 was developed. The analysis of intra- and interchromosome breakpoint distribution has been carried out on G-banded chromosomes, and results obtained were correlated with chromosome acetylated histone H4 profiles. A co-localization of intrachromosomal breakpoints induced by AluI, BamHI and DNase I as well as by neutrons and g-rays was observed. Radiation- and endonuclease-induced breakpoints tend to cluster in less condensed chromosome regions (G-light bands) that show the highest levels of acetylated histone H4. The analysis of interchromosomal distribution of radiation-induced lesions showed a concentration of breakpoints in Chinese hamster chromosomes with particular histone acetylation patterns. The fact that chromosome breakpoints occur more frequently in transcriptionally competent chromosome regions suggests that chromatin conformation and nuclear architecture could play a role in the distribution of chromosome lesions.
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Sun, Ramon C., Vikas V. Dukhande, Zhengqiu Zhou, Lyndsay E. A. Young, Shane Emanuelle, Christine Fillmore Brainson, and Matthew S. Gentry. "Nuclear Glycogenolysis Modulates Histone Acetylation in Human Non-Small Cell Lung Cancers." Cell Metabolism 30, no. 5 (November 2019): 903–16. http://dx.doi.org/10.1016/j.cmet.2019.08.014.
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Duncan, H. F., A. J. Smith, G. J. P. Fleming, and P. R. Cooper. "HDACi." Journal of Dental Research 90, no. 12 (May 2, 2011): 1377–88. http://dx.doi.org/10.1177/0022034511406919.
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Acetylation of histone and non-histone proteins alters gene expression and induces a host of cellular effects. The acetylation process is homeostatically balanced by two groups of cellular enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs). HAT activity relaxes the structure of the human chromatin, rendering it transcriptionally active, thereby increasing gene expression. In contrast, HDAC activity leads to gene silencing. The enzymatic balance can be ‘tipped’ by histone deacetylase inhibitors (HDACi), leading to an accumulation of acetylated proteins, which subsequently modify cellular processes including stem cell differentiation, cell cycle, apoptosis, gene expression, and angiogenesis. There is a variety of natural and synthetic HDACi available, and their pleiotropic effects have contributed to diverse clinical applications, not only in cancer but also in non-cancer areas, such as chronic inflammatory disease, bone engineering, and neurodegenerative disease. Indeed, it appears that HDACi-modulated effects may differ between ‘normal’ and transformed cells, particularly with regard to reactive oxygen species accumulation, apoptosis, proliferation, and cell cycle arrest. The potential beneficial effects of HDACi for health, resulting from their ability to regulate global gene expression by epigenetic modification of DNA-associated proteins, also offer potential for application within restorative dentistry, where they may promote dental tissue regeneration following pulpal damage.
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Li, Yuhong, Hui Huang, Man Zhu, Hua Bai, and Xiaowei Huang. "Roles of the MYST Family in the Pathogenesis of Alzheimer’s Disease via Histone or Non-histone Acetylation." Aging and disease 12, no. 1 (2021): 132. http://dx.doi.org/10.14336/ad.2020.0329.
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Gan, Yehua, Ying H. Shen, Jian Wang, Xinwen Wang, Budi Utama, Jing Wang, and Xing Li Wang. "Role of Histone Deacetylation in Cell-specific Expression of Endothelial Nitric-oxide Synthase." Journal of Biological Chemistry 280, no. 16 (February 19, 2005): 16467–75. http://dx.doi.org/10.1074/jbc.m412960200.
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Histone acetylation plays an important role in chromatin remodeling and gene expression. The molecular mechanisms involved in cell-specific expression of endothelial nitric-oxide synthase (eNOS) are not fully understood. In this study we investigated whether histone deacetylation was involved in repression of eNOS expression in non-endothelial cells. Induction of eNOS expression by histone deacetylase (HDAC) inhibitors trichostatin A (TSA) and sodium butyrate was observed in all four different types of non-endothelial cells examined. Chromatin immunoprecipitation assays showed that the induction of eNOS expression by TSA was accompanied by a remarkable increase of acetylation of histone H3 associated with the eNOS 5′-flanking region in the non-endothelial cells. Moreover, DNA methylation-mediated repression of eNOS promoter activity was partially reversed by TSA treatment, and combined treatment of TSA and 5-aza-2′-deoxycytidine (AzadC) synergistically induced eNOS expression in non-endothelial cells. The proximal Sp1 site is critical for basal activity of eNOS promoter. The induction of eNOS by inhibition of HDACs in non-endothelial cells, however, appeared not mediated by the changes in Sp1 DNA binding activity. We further showed that Sp1 bound to the endogenous eNOS promoter and associated with HDAC1 in non-endothelial HeLa cells. Combined TSA and AzadC treatment increased Sp1 binding to the endogenous eNOS promoter but decreased the association between HDAC1 and Sp1 in HeLa cells. Our data suggest that HDAC1 plays a critical role in eNOS repression, and the proximal Sp1 site may serve a key target for HDCA1-mediated eNOS repression in non-endothelial cells.
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Advani, Anjali, Sarah Gibson, Elizabeth Douglas, Tao Jin, Matt Kalaycio, Edward A. Copelan, Mikkael A. Sekeres, Ronald Sobecks, Shawnda Sungren, and Eric Hsi. "Histone H4 Acetylation as a Prognostic Factor for Patients with Acute Lymphocytic Leukemia in First Relapse." Blood 112, no. 11 (November 16, 2008): 1482. http://dx.doi.org/10.1182/blood.v112.11.1482.1482.
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Abstract Imbalances in histone acetylation can lead to changes in transcriptional dysregulation of genes involved in cell cycle progression and/or apoptosis. We have previously demonstrated that histone H4 acetylation is associated with improved relapse-free survival in newly diagnosed patients with acute lymphocytic leukemia (ALL) (Advani et al., ASH abstract #2798, 2007). However, the prognostic significance of histone acetylation in the relapsed setting is unclear. Therefore, we evaluated histone H4 acetylation in patients with ALL in first relapse, and the prognostic impact of acetylation on response to salvage therapy and overall survival (OS). Methods: From 1996 to 2007, patients with ALL in first relapse and an available diagnostic bone marrow biopsy performed at the Cleveland Clinic were evaluated. B5-fixed bone marrow core biopsies were reviewed for areas with the highest concentration of blasts. A tissue microarray was constructed using 1 mm tissue cores. The cores were arrayed in duplicate in the majority of samples. Immunohistochemistry was performed for acetyl-H4 (1:200 dilution; polyclonal; Upstate Biotech, Lake Placid, NY) using automated stainers and heat induced epitope retrieval. In each case, five hundred blasts were counted and only strong nuclear staining was classified as positive. Based on the distribution of cell counts, cases were classified as strongly positive if nuclear staining occurred in ≥ 40% of the blasts. Cytogenetic (CG) risk was defined by CALGB criteria. Cox proportional hazards analysis was used to identify univariate and multivariate risk factors for response to salvage therapy and OS at the time of relapse. Results: Thirty-nine patients had adequate tissue and clinical data for analysis. The median age at relapse was 39 yrs (range 20–67) and median time from diagnosis to first relapse was 13.2 months (range 1.4–39.0). Seventy-nine percent of patients had ALL derived from B-cell, 18% T-cell, and 3% mixed lineage. Thirty-one percent of patients had poor risk CG, 46% normal karyotype, 10% miscellaneous abnormalities, and 13% unknown CG. At the time of relapse, 13% of patients had central nervous system involvement in addition to blood/bone marrow disease. Thirty-three pts (85%) had acetylated histone H4. Most patients received re-induction with a high-dose cytarabine-based regimen (48%). However, the remainder received anthracycline/vincristine/prednisone (30%), methotrexate/vincristine/asparaginase/decadron (13%), or clofarabine/cytarabine (9%). Ten pts (26%) achieved a complete remission (CR) after salvage therapy. Nineteen pts (49%) proceeded to allogeneic bone marrow transplant (BMT) with a related or unrelated donor. The median OS for all patients was 6.1 months. The median OS for pts proceeding to BMT was superior to pts not proceeding to BMT (12.8 months versus 4.7 months, p<0.001). There was a trend towards an improved OS after relapse in patients with histone acetylation, HR=0.40, 95% CI 0.16–1.03, p=0.058 on univariate analysis. This trend remained on multivariate analysis when age, time from diagnosis to relapse, CG risk group, and immunophenotype were included in the analysis (HR=0.40, 95% CI 0.13–1.20, p=0.10). No patients with non-acetylated histone H4 were able to proceed to BMT because of refractory disease or death/complications related to salvage therapy. Conclusions: Acetylation of histone H4 is associated with a trend towards an improved OS in patients with ALL in relapse. This may be related to the fact that no patients with non-acetylated histone H4 were able to proceed to BMT. Although this data will need to be evaluated prospectively in a larger number of patients, this data provides rationale for the incorporation of histone deacetylase inibitors into salvage regimens for patients with relapsed/refractory ALL, particularly in patients not expressing acetylated histone H4.
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Kalff, Anna, Sridurga Mithraprabhu, Tiffany T. Khong, Malarmathy Ramachandran, Kate Reed, Hang Quach, Patricia A. Walker, Krystal Bergin, and Andrew Spencer. "A 2-Stage Phase II Study of Panobinostat Consolidation in Multiple Myeloma (MM) Patients with < CR Following Single High-Dose Chemotherapy (HDT) Conditioned Autologous Stem Cell Transplantation (ASCT) As Part of First Line Therapy." Blood 128, no. 22 (December 2, 2016): 4515. http://dx.doi.org/10.1182/blood.v128.22.4515.4515.
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Abstract Introduction Panobinostat is a pan-deacetylase inhibitor with activity against all class I, II, and IV histone deacetylase enzymes, including those implicated as potential targets in MM. Panobinostat increases acetylation of histones 2, 3 and 4 (H2, H3 and H4) and proteins involved in multiple oncogenic pathways, including the aggresome protein degradation pathway. Panobinostat has not been systematically evaluated as a single agent in patients with MM, however activity was demonstrated in patients with advanced MM in phase I and II trials. This, coupled with preclinical data, favorable toxicity profile and oral formulation strongly support its evaluation in a post-ASCT consolidation context. Aim To determine rate of conversion to CR/VGPR, to evaluate safety, toxicity and to document PFS/OS in MM patients treated with panobinostat consolidation post-ASCT. To identify a pharmacodynamic biomarker that can be utilised to select patients most likely to benefit from panobinostat by assessing changes in acetylation of lysine residues in H2A, H2B, H3 and H4. Methods Phase II, open label, single arm study. Newly diagnosed MM patients commenced panobinostat (45mg 3x per week, alternate weeks: 1 cycle = 4/52) 8-12 weeks (median 11) after a single MEL200 ASCT. Panobinostat continued until toxicity/relapse/progression. After 6 cycles (6C), patients were restaged and only continued if depth of response improved (conversion to CR/VGPR). Acetylation studies: PBMCs were collected at 3 time points - POST-ASCT, end of cycle 3 (EOC3) and end of cycle 6 (EOC6). CD3+ lymphocytes were assessed for changes in histone and tubulin acetylation in lysine (K) residues (H2A K5, H2B K5, H3 K9, H3 K14, H3 K18, H3 K27, H3 K56, H4 K5, H4 K8, H4 K12, H4 K16 and tubulin) by flow cytometry using mean fluorescence intensity (MFI) of the geometric mean. The MFI from a sample was normalized to the respective POST-ASCT sample and expressed as a fold difference. Results 24 patients (F=12, M=12), median age 58yrs (44-69), commenced panobinostat. Diagnosis ISS stage: I/II: 16, III: 8. 20/24 had diagnostic cytogenetics/FISH: 5 were poor risk (t(4;14), t(14;16), +1q21). After a median of 24m following panobinostat initiation (6-43m), 6 patients remain on therapy. Discontinuation was due to failure to improve depth of response (8), progression (6), non-compliance (2) and toxicity (2). 11 patients progressed, 2 died. Estimated 2 year PFS 65% (median PFS 25m, median OS NR). 22/24 patients completed at least 6C of therapy. 12/24 improved depth of response: VGPRàCR: 4, PRàVGPR: 7, PRàCR: 1; 4 patients within 0-3C, 8 patients within 3-6C. Two patients (one each from 0-3C and 3-6C groups) demonstrated a further reduction in tumour burden with maximal response occurring after EOC11 and EOC29. Median time to maximal response after was 4.6m after commencing panobinostat (1.2-29m). One patient who discontinued after EOC6 (failed to improve depth of response) had a further reduction in paraprotein from 5g/L to trace at 6m post EOC6 (sustained for 5m). All grade haematological toxicity: thrombocytopenia: 9/24 (grade 3/4 = 6), neutropenia: 7/24 (grade3 = 6), anaemia: 1/24. Principal non-haematological toxicities were GI [nausea: 22/24 (grade 3 = 3), diarrhoea: 22/24 (grade 3=4)], fatigue: 18/22 and infection: 15/22 (grade 3=9). Only 5/24 patients tolerated dosing as per protocol. The median tolerated dose was 25mg. Changes in histone acetylation were assessed for 11 responders and 5 non-responders. Responders demonstrated increasing levels of acetylation at EOC3 and EOC6: At EOC3, this was most marked for H2B K5, H3 K9, H3 K14, H3 K56, H4 K8, H4 K12, H4 K16 at EOC3, while at EOC6, all histone acetylation lysine residues tested were significantly increased compared to POST-ASCT. In contrast, there were no differences in the levels of acetylation for either EOC3 or EOC6 compared to POST-ASCT for the non-responders. The differences in observed changes in histone acetylation seen at EO6 in responders compared to non-responders were significant. Conclusion Single agent panobinostat consolidation post-ASCT improves depth of response in a non-favourable group of patients, and in some patients, induces a further reduction in tumour burden beyond 12m post-ASCT Assessment of histone acetylation changes represents a pharmacodynamic biomarker of clinical benefit, with a strong correlation between the levels of acetylation and response of the patient to panobinostat. Disclosures Quach: Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.
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Panayiotidis, Mihalis. "Cruciferous Vegetables-Based Isothiocyanate Compounds as Novel Epigenetic Modulators in Human Malignant Melanoma." Medical Sciences Forum 2, no. 1 (December 3, 2020): 10. http://dx.doi.org/10.3390/cahd2020-08892.
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Among the various types of dietary agents, isothiocyanates (ITCs) have raised scientific interest with their unique properties against disease development, including modulation of the epigenetic machinery. In the context of malignant melanoma (MM), our research efforts have aimed to understand how ITCs induce cell death by interacting with the epigenetic machinery and thus leading to inhibition of tumor growth. For this purpose, we have utilized an in vitro model of human MM consisting of normal keratinocytes, primary and metastatic melanoma as well as non-melanoma epidermoid carcinoma cell lines. In this model, specific ITCs (e.g., sulforaphane (SFN), iberin (IBN) and allyl isothiocyanate (AITC)) were examined for their ability to influence histone acetylation and methylation marks, as a potential epigenetic therapeutic strategy against MM. Overall, we report that all ITCs inhibited MM cell proliferation and influenced acetylation and methylation status of specific lysine residues on H3 and H4 by modulating the expression of various histone acetyl transferases (HATs), histone deacetylases (HDACs) and histone methyl transferases (HMTs) in MM cells. Our data highlight novel insights on SFN, IBN and AITC interaction with components of the histone regulatory machinery, to exert their anticancer action in MM.
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Xu, Qiutao, Qian Liu, Zhengting Chen, Yaping Yue, Yuan Liu, Yu Zhao, and Dao-Xiu Zhou. "Histone deacetylases control lysine acetylation of ribosomal proteins in rice." Nucleic Acids Research 49, no. 8 (April 9, 2021): 4613–28. http://dx.doi.org/10.1093/nar/gkab244.
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Abstract Lysine acetylation (Kac) is well known to occur in histones for chromatin function and epigenetic regulation. In addition to histones, Kac is also detected in a large number of proteins with diverse biological functions. However, Kac function and regulatory mechanism for most proteins are unclear. In this work, we studied mutation effects of rice genes encoding cytoplasm-localized histone deacetylases (HDAC) on protein acetylome and found that the HDAC protein HDA714 was a major deacetylase of the rice non-histone proteins including many ribosomal proteins (r-proteins) and translation factors that were extensively acetylated. HDA714 loss-of-function mutations increased Kac levels but reduced abundance of r-proteins. In vitro and in vivo experiments showed that HDA714 interacted with r-proteins and reduced their Kac. Substitutions of lysine by arginine (depleting Kac) in several r-proteins enhance, while mutations of lysine to glutamine (mimicking Kac) decrease their stability in transient expression system. Ribo-seq analysis revealed that the hda714 mutations resulted in increased ribosome stalling frequency. Collectively, the results uncover Kac as a functional posttranslational modification of r-proteins which is controlled by histone deacetylases, extending the role of Kac in gene expression to protein translational regulation.
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Lombó, Marta, and María Paz Herráez. "Paternal Inheritance of Bisphenol A Cardiotoxic Effects: The Implications of Sperm Epigenome." International Journal of Molecular Sciences 22, no. 4 (February 20, 2021): 2125. http://dx.doi.org/10.3390/ijms22042125.
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Parental exposure to bisphenol A (BPA) has been linked to a greater incidence of congenital diseases. We have demonstrated that BPA induces in zebrafish males an increase in the acetylation of sperm histones that is transmitted to the blastomeres of the unexposed progeny. This work is aimed to determine whether histone hyperacetylation promoted by paternal exposure to BPA is the molecular mechanism underlying the cardiogenesis impairment in the descendants. Zebrafish males were exposed to 100 and 2000 µg/L BPA during early spermatogenesis and mated with non-exposed females. We analyzed in the progeny the expression of genes involved in cardiogenesis and the epigenetic profile. Once the histone hyperacetylation was confirmed, treatment with epigallocatechin gallate (EGCG), an inhibitor of histone acetyltransferases, was assayed on F1 embryos. Embryos from males exposed to 2000 µg/L BPA overexpressed the transcription factor hand2 and the receptor esr2b, showing their own promoters—as well as that of kat6a—an enrichment in H3K9ac. In embryos treated with EGCG, both gene expression and histone acetylation (global and specific) returned to basal levels, and the phenotype was recovered. As shown by the results, the histone hyperacetylated landscape promoted by BPA in the sperm alters the chromatin structure of the progeny, leading to the overexpression of the histone acetyltransferase and genes involved in cardiogenesis.
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He, Zhihui, Huaihuai Peng, Min Gao, Guibin Liang, Menghao Zeng, and Xuefeng Zhang. "p300/Sp1-Mediated High Expression of p16 Promotes Endothelial Progenitor Cell Senescence Leading to the Occurrence of Chronic Obstructive Pulmonary Disease." Mediators of Inflammation 2021 (August 19, 2021): 1–17. http://dx.doi.org/10.1155/2021/5599364.
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Objective. Chronic obstructive pulmonary disease (COPD) is a common chronic disease and develops rapidly into a grave public health problem worldwide. However, what exactly causes the occurrence of COPD remains largely unclear. Here, we are trying to explore whether the high expression of p16 mediated by p300/Sp1 can cause chronic obstructive pulmonary disease through promoting the senescence of endothelial progenitor cells (EPCs). Methods. Peripheral blood EPCs were isolated from nonsmoking non-COPD, smoking non-COPD, and smoking COPD patients. The expressions of p16, p300, and senescence-related genes were detected by RT-PCR and Western Blot. Then, we knocked down or overexpressed Sp1 and p300 and used the ChIP assay to detect the histone H4 acetylation level in the promoter region of p16, CCK8 to detect cell proliferation, flow cytometry to detect the cell cycle, and β-galactosidase staining to count the proportion of senescent cells. Results. The high expression of p16 was found in peripheral blood EPCs of COPD patients; the cigarette smoke extract (CSE) led to the increase of p16. The high expression of p16 in EPCs promoted cell cycle arrest and apoptosis. The CSE-mediated high expression of p16 promoted cell senescence. The expression of p300 was increased in peripheral blood EPCs of COPD patients. Moreover, p300/Sp1 enhanced the histone H4 acetylation level in the promoter region of p16, thereby mediating the senescence of EPCs. And knockdown of p300/Sp1 could rescue CSE-mediated cell senescence. Conclusion. p300/Sp1 enhanced the histone H4 acetylation level in the p16 promoter region to mediate the senescence of EPCs.
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Ren, Jingjing, Eric Panther, Xiaofeng Liao, Amrie Grammer, Peter Lipsky, and Chris Reilly. "The Impact of Protein Acetylation/Deacetylation on Systemic Lupus Erythematosus." International Journal of Molecular Sciences 19, no. 12 (December 12, 2018): 4007. http://dx.doi.org/10.3390/ijms19124007.
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Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease in which the body’s immune system mistakenly attacks healthy cells. Although the exact cause of SLE has not been identified, it is clear that both genetics and environmental factors trigger the disease. Identical twins have a 24% chance of getting lupus disease if the other one is affected. Internal factors such as female gender and sex hormones, the major histocompatibility complex (MHC) locus and other genetic polymorphisms have been shown to affect SLE, as well as external, environmental influences such as sunlight exposure, smoking, vitamin D deficiency, and certain infections. Several studies have reported and proposed multiple associations between the alteration of the epigenome and the pathogenesis of autoimmune disease. Epigenetic factors contributing to SLE include microRNAs, DNA methylation status, and the acetylation/deacetylation of histone proteins. Additionally, the acetylation of non-histone proteins can also influence cellular function. A better understanding of non-genomic factors that regulate SLE will provide insight into the mechanisms that initiate and facilitate disease and also contribute to the development of novel therapeutics that can specifically target pathogenic molecular pathways.
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LoPresti, Patrizia. "HDAC6 in Diseases of Cognition and of Neurons." Cells 10, no. 1 (December 23, 2020): 12. http://dx.doi.org/10.3390/cells10010012.
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Central nervous system (CNS) neurodegenerative diseases are characterized by faulty intracellular transport, cognition, and aggregate regulation. Traditionally, neuroprotection exerted by histone deacetylase (HDAC) inhibitors (HDACi) has been attributed to the ability of this drug class to promote histone acetylation. However, HDAC6 in the healthy CNS functions via distinct mechanisms, due largely to its cytoplasmic localization. Indeed, in healthy neurons, cytoplasmic HDAC6 regulates the acetylation of a variety of non-histone proteins that are linked to separate functions, i.e., intracellular transport, neurotransmitter release, and aggregate formation. These three HDAC6 activities could work independently or in synergy. Of particular interest, HDAC6 targets the synaptic protein Bruchpilot and neurotransmitter release. In pathological conditions, HDAC6 becomes abundant in the nucleus, with deleterious consequences for transcription regulation and synapses. Thus, HDAC6 plays a leading role in neuronal health or dysfunction. Here, we review recent findings and novel conclusions on the role of HDAC6 in neurodegeneration. Selective studies with pan-HDACi are also included. We propose that an early alteration of HDAC6 undermines synaptic transmission, while altering transport and aggregation, eventually leading to neurodegeneration.
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Thakur, Basant Kumar, Tino Dittrich, Karl Welte, Jan-Henning Klusmann, and Dirk Reinhardt. "Acetylation of p53 Is Involved in Valproic Acid Induced Death of AML Cells." Blood 118, no. 21 (November 18, 2011): 2461. http://dx.doi.org/10.1182/blood.v118.21.2461.2461.
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Abstract Abstract 2461 Introduction: Impaired acetylation level of histone and non-histone proteins, due to increased histone deacetylase (HDAC) activity relates to pathological malignancies including leukemias. The tumor suppressor protein p53 is an important non-histone target of HDACs and regulates key cellular processes such as DNA repair, cell-cycle arrest, senescence and apoptosis. The p53 protein undergoes several post-translational modification and among them acetylation allows p53 to induce the expression of genes relevant to tumor suppression. In certain cases of leukemias, overexpression of HDACs has been associated with inactivation of p53 via deacetylation. Therefore, increasing the acetylation of p53 by inhibition of HDACs can be an effective approach to trigger the function of p53 in cancer cells. The anticonvulsant valproic acid (VPA) has been shown to be an efficient HDAC inhibitor (HDACI), able to induce apoptosis in acute myeloid leukemia (AML) cells, and has recently entered clinical trials as a potential therapeutic agent. Although VPA exerts strong anti-tumor activity against haematological malignancies, the molecular mechanism of events involved in VPA-mediated death of leukemia cells is largely unclear. Methods/results: To identify the potential downstream targets triggered by VPA in leukemia cells, the acetylation profile in total cell lysate was compared between VPA treated and untreated NB4 leukemia cell line. We observed increased acetylation of several proteins ranging from 20 KDa to 150 KDa after VPA treatment. Among them acetylation of p53 at lysine residue 382, critical for p53 function, was detected. This result motivated us to further elucidate the functional significance of p53 acetylation in leukemia cells. VPA mediated p53 acetylation resulted in more than two fold induction of several p53 target genes, such as p21, BAX, GADD45A. By knockdown of p53 using specific shRNA against mRNA of p53 we show that VPA mediated expression of p21 was independent of p53, in contrast VPA mediated expression of BAX required presence of p53. Activation of p53 by VPA involved increased expression of genes involved in cell-cycle arrest and apoptosis. Therefore we performed cell cycle analysis using BrdU and evaluated apoptosis by Annexin V staining after challenging the leukemia cells with VPA (0.5 mM, 1mM and 2mM). We observed a dose dependent decrease of cells entering S-phase and this was accompanied by increase of cells undergoing cell cycle arrest and apoptosis. VPA induced apoptosis and cell cycle arrest was significantly attenuated in p53 knock down cells, indicating p53 as an active player in VPA mediated killing of leukemic cells. To further address the clinical relevance of VPA mediated p53 signalling, we performed experiments with primary blasts isolated from AML patients (n = 10). Treatment with 1mM VPA imposed cytotoxic effect on all leukemia cells tested with varying intensities (6 high responsive and 4 low responsive). Acetylation of p53 was dramatically increased in the six patient samples which were highly sensitive to VPA in contrast to 4 patient samples which were less responsive. Furthermore increased acetylation of p53 in these blast samples was subsequently associated with increased mRNA expression of both p21 and BAX. Conclusion: In summary we demonstrate that p53 is an important player downstream of VPA signaling and suggest that induction of p53 acetylation by VPA plays a decisive role in imposing cytotoxic effect on AML cells. Disclosures: No relevant conflicts of interest to declare.
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Pastorelli, Roberta, Germano Ferrari, Antonella Gozzini, Donatella Tombaccini, Valeria Santini, and Alberto Bosi. "CML Blasts Modify the Acetylation Pattern of Non Histone Proteins after Short Chain Fatty Acid Histone Deacetylase Inhibitor Treatment." Blood 106, no. 11 (November 16, 2005): 2884. http://dx.doi.org/10.1182/blood.v106.11.2884.2884.
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Abstract Imatinib is an effective therapy for chronic phase CML, but patients may became irresponsive due to the development of resistance, caused by amplification of the BCR-ABL genomic locus or by point mutations within the kinase domain of BCR-ABL, which prevents drug binding. Novel dual SRC/ABL kinase inhibitors with higher potency against native and imatinib-resistant mutants of BCR-ABL have substantial clinical utility, but at least one mutation remains resistant to any kinase inhibitor (T315I). Thus, the search for alternative drugs effective in CML is still cogent. Treatment of CML cells with histone deacetylase inhibitors (HDIs) of the class of hydroxamic acid analogues promotes proteasomal degradation of Bcr-Abl, associated with apoptosis, in synergy with imatinib. We evaluated whether HDIs of other classes, namely short chain fatty acids like butyrates and valproic acid, could exert the same effects and we intended to dissect the determining molecular mechanisms. The human CML cell lines K562, KBM, LAMA-84 S and LAMA-84 R and primary imatinib-resistant CML-BC cells were grown in the presence of valproic acid (VPA) at the escalating doses 0.2 mM to 2mM or the mannose ester of butyric acid D1 (0.2–1mM) for 24 and 48 hrs. Apoptosis was induced in a time and dose dependent manner by VPA and D1 (annexin V test and flow cytometric analysis after propidium iodide uptake). Imatinib was synergistic with both HDIs in inducing apoptosis and cell proliferation arrest (MTT-assay). VPA and D1 were able to induce after 48 hrs of incubation a significant decrease in the number of copies of BCR-ABL determined by real time-PCR, paralleled by a substantial decrease in Bcr-Abl protein expression, shown in western blots of total cell lysates from CML cells. This decrease in the expression of protein kinase could account for the synergy with imatinib, but also for the reversal of resistance in mutated Bcr-Abl CML cells and is consistent with what previously observed. We also analysed the expression of Hsp-90 (protein chaperone of Bcr-Abl) and found it quantitatively unmodified but hyperacetylated by the treatment with both HDIs. As little is known of the ability of short chain fatty acids to induce acetylation of non-histone proteins, we compared the acetylated proteome of CML cells treated and not treated with HDIs, alone and in combination with imatinib, by 2D western blot versus a pan-acetylated antibody, followed by MALDI-TOF mass spectrometry for protein identification. 22 proteins were positively identified with a high degree of confidence, with the majority of these being cytoplasmic. At least two chaperone proteins were identified as target of acetylation after VPA and D1 treatment of CML cells, other targets were proteins involved in the synthesis and stability of RNA. Phosphorylation of proteins, evaluated by 2D western blot, was not significantly affected by HDIs. Short chain fatty acids are indeed not the most potent HDIs, but have been used successfully in clinical trials. Our observations contribute to the dissection of proteome modifications by HDIs and may help extrapolate the molecular effects of different HDIs on CML cells so to improve their use as single drugs or in combination with imatinib or new SRC/ABL inhibitors.
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Ryan, J., A. J. Llinas, D. A. White, B. M. Turner, and J. Sommerville. "Maternal histone deacetylase is accumulated in the nuclei of Xenopus oocytes as protein complexes with potential enzyme activity." Journal of Cell Science 112, no. 14 (July 15, 1999): 2441–52. http://dx.doi.org/10.1242/jcs.112.14.2441.
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Reversible acetylation of core histones plays an important regulatory role in transcription and replication of chromatin. The acetylation status of chromatin is determined by the equilibrium between activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). The Xenopus protein HDACm shows sequence homology to other putative histone deacetylases, but its mRNA is expressed only during early development. Both HDACm protein and acetylated non-chromosomal histones are accumulated in developing oocytes, indicating that the key components for histone deposition into new chromatin during blastula formation are in place by the end of oogenesis. Here we show that the 57 kDa HDACm protein undergoes steady accumulation in the nucleus, where it is organized in a multiprotein complex of approx. 300 kDa. A second, major component of the nuclear complex is the retinoblastoma-associated protein p48 (RbAp48/46), which may be used as an adaptor to contact acetylated histones in newly assembled chromatin. The nuclear complex has HDAC activity that is sensitive to trichostatin A, zinc ions and phosphatase treatment. The 57 kDa protein serves as a marker for total HDAC activity throughout oogenesis and early embryogenesis. The active HDACm complex and its acetylated histone substrates appear to be kept apart until after chromatin assembly has taken place. However, recombinant HDACm, injected into the cytoplasm of oocytes, not only is translocated to the nucleus, but also is free to interact with the endogenous chromatin.
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Vyskot, Boris, Jiri Siroky, Renata Hladilova, Nikolai D. Belyaev, and Bryan M. Turner. "Euchromatic domains in plant chromosomes as revealed by H4 histone acetylation and early DNA replication." Genome 42, no. 2 (April 1, 1999): 343–50. http://dx.doi.org/10.1139/g98-133.
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Using specific polyclonal antisera raised against acetylated isoforms of histone H4, we have analyzed their distribution in the dioecious plant Silene latifolia (syn.Melandrium album) possessing heteromorphic sex chromosomes. Our previous studies on this species have shown that one of the two X chromosomes in homogametic female cells is heavily methylated and late replicating, as a possible consequence of dosage compensation. Here we report that there are no detectable differences in intensity and distribution of H4 acetylation between these two X chromosomes. In S. latifolia only distal-subtelomeric chromosome regions, on both the sex chromosomes and autosomes, display strong signals of H4 acetylation at N-terminal lysines 5, 8, and 12. These acetylated domains correspond to the very early replicating distal chromosome regions as revealed by 5-bromodeoxyuridine pulses followed by the indirect immunofluorescence microscopy. The distribution of H4 acetylated at lysine 16 was uniform along the chromosomes. The unique distal-subtelomeric H4 acetylation signals were also observed in three other Silene species (S. vulgaris, S. pendula, andS. chalcedonica), but not in two non-related plant species tested (Allium cepa and Nicotiana tabacum). The presented data as well as our recent studies on the structure of S. latifolia chromosome ends indicate that Silene species possess the specific distal-subtelomeric location of euchromatin, gene-rich regions on chromosomes.Key words: histone H4 acetylation, DNA replication, euchromatin, immunofluorescence labeling, Silene spp.
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Xiao, Liyun, Xudong Ma, Yiqun Huang, Ruiji Zhen, Xiaoling Ye, Jen-Wei Chiao, and Delong Liu. "The Epigenetic Effect of Phenylhexyl Isothiocyanate on Histone Acetylation in Patients with Acute Leukemia and Non-Leukemic Disorders." Blood 110, no. 11 (November 16, 2007): 4145. http://dx.doi.org/10.1182/blood.v110.11.4145.4145.
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Abstract Phenyhexyl isothiocyanate (PHI) has been shown to inhibit histone deacetylation in leukemia cell lines in vitro and in animal models. In this study we examined the histone acetylation status in leukemia cells from patients with acute leukemia as well as in non-leukemia cells. From January to September 2006, 19 patients with newly diagnosed acute leukemia were enrolled. 12 patients had AML, 7 had ALL. The age ranged between 2 months to 65 years old. There were 12 males and 7 females among them. 5 non- leukemia patients were also enrolled, with 1 anemia, 1 infection disease, 2 ITP, and 1 healthy volunteer. Mononuclear cells were isolated from patients’ specimen. Apoptosis of the cells and histone acetylation of H3 and H4 were characterized pre- and post- PHI treatment. The expression of acetylated H3 and H4 in acute leukemia cells was decreased, as compared to those in non-leukemia cells. Increased apoptosis was seen in the acute leukemia cells after PHI treatment of the primary culture of the leukemia cells for 3 and 7 hours. The effect of PHI on the leukemia cells from patients was time- and dose-dependent. There was a significant increase of PHI effect on leukemia cells versus non-leukemia cells (p<0.05), suggesting that PHI may have preferential activity against leukemia cells. This study presents the first evidence of PHI with preferential activity against leukemia cells over non-leukemia cells from human subjects. Clinical trial is warranted to study PHI in leukemia patients.
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Giuliano, Michela, Claudia Pellerito, Adriana Celesia, Tiziana Fiore, and Sonia Emanuele. "Tributyltin(IV) Butyrate: A Novel Epigenetic Modifier with ER Stress- and Apoptosis-Inducing Properties in Colon Cancer Cells." Molecules 26, no. 16 (August 19, 2021): 5010. http://dx.doi.org/10.3390/molecules26165010.
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Organotin(IV) compounds are a class of non-platinum metallo-conjugates exhibiting antitumor activity. The effects of different organotin types has been related to several mechanisms, including their ability to modify acetylation protein status and to promote apoptosis. Here, we focus on triorganotin(IV) complexes of butyric acid, a well-known HDAC inhibitor with antitumor properties. The conjugated compounds were synthesized and characterised by FTIR spectroscopy, multi-nuclear (1H, 13C and 119Sn) NMR, and mass spectrometry (ESI-MS). In the triorganotin(IV) complexes, an anionic monodentate butyrate ligand was observed, which coordinated the tin atom on a tetra-coordinated, monomeric environment similar to ester. FTIR and NMR findings confirm this structure both in solid state and solution. The antitumor efficacy of the triorganotin(IV) butyrates was tested in colon cancer cells and, among them, tributyltin(IV) butyrate (BT2) was selected as the most efficacious. BT2 induced G2/M cell cycle arrest, ER stress, and apoptotic cell death. These effects were obtained using low concentrations of BT2 up to 1 μM, whereas butyric acid alone was completely inefficacious, and the parent compound TBT was poorly effective at the same treatment conditions. To assess whether butyrate in the coordinated form maintains its epigenetic effects, histone acetylation was evaluated and a dramatic decrease in acetyl-H3 and -H4 histones was found. In contrast, butyrate alone stimulated histone acetylation at a higher concentration (5 mM). BT2 was also capable of preventing histone acetylation induced by SAHA, another potent HDAC inhibitor, thus suggesting that it may activate HDACs. These results support a potential use of BT2, a novel epigenetic modulator, in colon cancer treatment.
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Gupta, Mamta, Jing Jing Han, Mary Stenson, Linda Wellik, and Thomas E. Witzig. "HDAC Class I Inhibition Acetylates a Non-Histone Protein STAT3 by Modulating p300-STAT3-HDAC1 Interaction In Activated B- Cell Like (ABC) Diffuse Large B Cell Lymphoma." Blood 116, no. 21 (November 19, 2010): 115. http://dx.doi.org/10.1182/blood.v116.21.115.115.
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Abstract Abstract 115 Patients with diffuse large B- cell lymphoma (DLBCL) tumors that have an activated B-cell like (ABC) gene expression profile have a poorer prognosis. Understanding the mechanism(s) used by ABC tumor cells to resist the effects of common chemotherapy agents may lead to alternative approaches for the treatment of these tumors. ABC cell lines have been shown to have high levels of phosphorylated STAT3 (pSTAT3); however, the mechanisms that regulate STAT3 signaling in ABC DLBCL remain unclear. Histone deacetylases (HDACs) are enzymes that can deacetylate both non-histone and histone substrates. In this study we tested the hypothesis that HDACs in the tumor cells target a non-histone protein STAT3 in ABC DLBCL. In studies of HDAC expression in DLBCL tumors, we found over-expression of the type 1 HDACs, specifically HDAC1and HDAC3, in the pSTAT3- positive ABC tumors as compared to germinal centre B like (GCB) tumors. We then performed a co-immunoprecipitation (Co-IP) assay to learn the functional interaction between STAT3 and HDAC1. We found that STAT3 formed complexes with HDAC1 or HDAC3. Further Co-IP studies demonstrated that p300, a histone acetyltransferase (HAT), STAT3, and HDAC1 are all in the same complex. To determine whether p300 acetylates STAT3 in ABC cells, we immuno-precipitated endogenous p300 and blotted with acetylated STAT3 and showed that p300 acetylates STAT3 at lysine 685. We next tested whether HDAC inhibition could affect p300 mediated STAT3 acetylation in ABC cells. Inhibition of HDAC activity through the HDAC inhibitor LBH589 (LBH, Novartis Pharmaceuticals) increased STAT3 acetylation in a dose- dependent manner. Similar results were obtained when we used antiacetyl- lysine antibody. Furthermore HDAC1 over-expression inhibits STAT3 acetylation at lysine 685. This data implies a tight regulation of STAT3 acetylation and deacetylases in vivo in ABC lymphoma. In addition to acetylation, STAT3 can be modified by phosphorylation, thus the effect of HDAC inhibition on pSTAT3 both at serine and tyrosine residues was studied. We observed a dose-dependent decrease in pSTAT3 with some inhibitory effect on total STAT3. LBH was found to mediate STAT3 dephosphorylation by inhibiting the tyrosine phosphorylation of JAK2 and TYK2, the STAT3 upstream activators, in a dose- dependent manner. Since ABC lymphoma has higher levels of HDAC1 or HDAC3 and pSTAT3/STAT3 than GCB, we hypothesized that ABC cells will be more sensitive to HDAC inhibition than GCB. In fact, when ABC and GCB DLBCL cells were treated with LBH we observed that LBH was more cytotoxic to ABC than GCB as evidenced by annexin/PI staining and PARP cleavage. LD90 was 25 nM for ABC cells, however GCB cells required 5 times more LBH to kill 90% cells. STAT3 activation regulates genes involved in cell survival, including Bcl-2, Mcl-1, Bcl-XL, and c-Myc. LBH treatment resulted in down-regulation of Mcl-1 and c-Myc in ABC cells but has no effect in GCB cells; however, Bcl-2 and Bcl-XL levels were not decreased in both the subtype. Having established that HDAC1 physically associated with STAT3 and that LBH treatment elevated STAT3 acetylation in ABC cells, we proceeded to deplete endogenous HDAC1 with siRNA in Ly3 cells and found that HDAC1 knockdown up-regulated STAT3 acetylation indicating that HDAC1 negatively regulates the acetylation in vivo. HDAC1 inhibition also prevented phopshorylation of STAT3 and induces aopotosis in ABC cells. In summary, we have demonstrated that a key consequence of HATs and HDACs expression and activity is modulation of the STAT3 pathway in ABC lymphoma. Inhibition of this pathway with the HDAC inhibitor LBH inhibits constitutive STAT3 signaling and induces Mcl-1 mediated apoptosis. These studies provide the rationale for targeting the poorly responsive ABC-type DLBCL by inhibiting HDAC activity with epigenetic inhibitors such as LBH. We are currently testing LBH589 in relapsed DLBCL in a phase I clinical trial. Disclosures: No relevant conflicts of interest to declare.
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Collas, P., M. R. Liang, M. Vincent, and P. Alestrom. "Active transgenes in zebrafish are enriched in acetylated histone H4 and dynamically associate with RNA Pol II and splicing complexes." Journal of Cell Science 112, no. 7 (April 1, 1999): 1045–54. http://dx.doi.org/10.1242/jcs.112.7.1045.
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We have investigated the functional organization of active and silent integrated luciferase transgenes in zebrafish, with the aim of accounting for the variegation of transgene expression in this species. We demonstrate the enrichment of transcriptionally active transgenes in acetylated histone H4 and the dynamic association of the transgenes with splicing factor SC35 and RNA Pol II. Analysis of interphase nuclei and extended chromatin fibers by immunofluorescence and in situ hybridization reveals a co-localization of transgenes with acetylated H4 in luciferase-expressing animals only. Enrichment of expressed transgenes in acetylated H4 is further demonstrated by their co-precipitation from chromatin using anti-acetylated H4 antibodies. Little correlation exists, however, between the level of histone acetylation and the degree of transgene expression. In transgene-expressing zebrafish, most transgenes co-localize with Pol II and SC35, whereas no such association occurs in non-expressing individuals. Inhibition of Pol II abolishes transgene expression and disrupts association of transgenes with SC35, although inactivated transgenes remains enriched in acetylated histones. Exposure of embryos to the histone deacetylation inhibitor TSA induces expression of most silent transgenes. Chromatin containing activated transgenes becomes enriched in acetylated histones and the transgenes recruit SC35 and Pol II. The results demonstrate a correlation between H4 acetylation and transgene activity, and argue that active transgenes dynamically recruit splicing factors and Pol II. The data also suggest that dissociation of splicing factors from transgenes upon Pol II inhibition is not a consequence of changes in H4 acetylation.
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Yang, Feikun, Ru Hao, Barbara Kessler, Gottfried Brem, Eckhard Wolf, and Valeri Zakhartchenko. "Rabbit somatic cell cloning: effects of donor cell type, histone acetylation status and chimeric embryo complementation." Reproduction 133, no. 1 (January 2007): 219–30. http://dx.doi.org/10.1530/rep.1.01206.
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The epigenetic status of a donor nucleus has an important effect on the developmental potential of embryos produced by somatic cell nuclear transfer (SCNT). In this study, we transferred cultured rabbit cumulus cells (RCC) and fetal fibroblasts (RFF) from genetically marked rabbits (Alicia/Basilea) into metaphase II oocytes and analyzed the levels of histone H3-lysine 9-lysine 14 acetylation (acH3K9/14) in donor cells and cloned embryos. We also assessed the correlation between the histone acetylation status of donor cells and cloned embryos and their developmental potential. To test whether alteration of the histone acetylation status affects development of cloned embryos, we treated donor cells with sodium butyrate (NaBu), a histone deacetylase inhibitor. Further, we tried to improve cloning efficiency by chimeric complementation of cloned embryos with blastomeres fromin vivofertilized or parthenogenetic embryos. The levels of acH3K9/14 were higher in RCCs than in RFFs (P<0.05). Although the type of donor cells did not affect development to blastocyst, after transfer into recipients, RCC cloned embryos induced a higher initial pregnancy rate as compared to RFF cloned embryos (40 vs 20%). However, almost all pregnancies with either type of cloned embryos were lost by the middle of gestation and only one fully developed, live RCC-derived rabbit was obtained. Treatment of RFFs with NaBu significantly increased the level of acH3K9/14 and the proportion of nuclear transfer embryos developing to blastocyst (49 vs 33% with non-treated RFF,P<0.05). The distribution of acH3K9/14 in either group of cloned embryos did not resemble that inin vivofertilized embryos suggesting that reprogramming of this epigenetic mark is aberrant in cloned rabbit embryos and cannot be corrected by treatment of donor cells with NaBu. Aggregation of embryos cloned from NaBu-treated RFFs with blastomeres fromin vivoderived embryos improved development to blastocyst, but no cloned offspring were obtained. Two live cloned rabbits were produced from this donor cell type only after aggregation of cloned embryos with a parthenogenetic blastomere. Our study demonstrates that the levels of histone acetylation in donor cells and cloned embryos correlate with their developmental potential and may be a useful epigenetic mark to predict efficiency of SCNT in rabbits.
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Kim, Min Young, Bowen Yan, Suming Huang, and Yi Qiu. "Regulating the Regulators: The Role of Histone Deacetylase 1 (HDAC1) in Erythropoiesis." International Journal of Molecular Sciences 21, no. 22 (November 11, 2020): 8460. http://dx.doi.org/10.3390/ijms21228460.
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Histone deacetylases (HDACs) play important roles in transcriptional regulation in eukaryotic cells. Class I deacetylase HDAC1/2 often associates with repressor complexes, such as Sin3 (Switch Independent 3), NuRD (Nucleosome remodeling and deacetylase) and CoREST (Corepressor of RE1 silencing transcription factor) complexes. It has been shown that HDAC1 interacts with and modulates all essential transcription factors for erythropoiesis. During erythropoiesis, histone deacetylase activity is dramatically reduced. Consistently, inhibition of HDAC activity promotes erythroid differentiation. The reduction of HDAC activity not only results in the activation of transcription activators such as GATA-1 (GATA-binding factor 1), TAL1 (TAL BHLH Transcription Factor 1) and KLF1 (Krüpple-like factor 1), but also represses transcription repressors such as PU.1 (Putative oncogene Spi-1). The reduction of histone deacetylase activity is mainly through HDAC1 acetylation that attenuates HDAC1 activity and trans-repress HDAC2 activity through dimerization with HDAC1. Therefore, the acetylation of HDAC1 can convert the corepressor complex to an activator complex for gene activation. HDAC1 also can deacetylate non-histone proteins that play a role on erythropoiesis, therefore adds another layer of gene regulation through HDAC1. Clinically, it has been shown HDACi can reactivate fetal globin in adult erythroid cells. This review will cover the up to date research on the role of HDAC1 in modulating key transcription factors for erythropoiesis and its clinical relevance.
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Khan, Ahlia N., and Peter N. Lewis. "Unstructured Conformations Are a Substrate Requirement for the Sir2 Family of NAD-dependent Protein Deacetylases." Journal of Biological Chemistry 280, no. 43 (August 29, 2005): 36073–78. http://dx.doi.org/10.1074/jbc.m508247200.
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The regulation of protein function is often achieved through post-translational modifications including phosphorylation, methylation, ubiquitination, and acetylation. The role of acetylation has been most extensively studied in the context of histones, but it is becoming increasingly evident that this modification now includes other proteins. The Sir2 family of NAD-dependent deacetylases was initially recognized as mediating gene silencing through histone deacetylation, but several family members display non-nuclear sub-cellular localization and deacetylate non-histone protein substrates. Although many structural and enzymatic studies of Sir2 proteins have been reported, how substrate recognition is achieved by this family of enzymes is unknown. Here we use in vitro deacetylase assays and a variety of potential substrates to examine the substrate specificity of yeast homologue Hst2. We show that Hst2 is specific for acetyl-lysine within proteins; it does not deacetylate small polycations such as acetyl-spermine or acetylated amino ter-mini of proteins. Furthermore we have found that Hst2 displays conformational rather than sequence specificity, preferentially deacetylating acetyl-lysine within unstructured regions of proteins. Our results suggest that this conformational requirement may be a general feature for substrate recognition in the Sir2 family.