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Friedman J Cho WK Chu CK Keedy KS Archin NM Margolis DM Karn J 《Journal of virology》2011,85(17):9078-9089
Latent HIV proviruses are silenced as the result of deacetylation and methylation of histones located at the viral long terminal repeat (LTR). Inhibition of histone deacetylases (HDACs) leads to the reemergence of HIV-1 from latency, but the contribution of histone lysine methyltransferases (HKMTs) to maintaining HIV latency remains uncertain. Chromatin immunoprecipitation experiments using latently infected Jurkat T-cell lines demonstrated that the HKMT enhancer of Zeste 2 (EZH2) was present at high levels at the LTR of silenced HIV proviruses and was rapidly displaced following proviral reactivation. Knockdown of EZH2, a key component of the Polycomb repressive complex 2 (PRC2) silencing machinery, and the enzyme which is required for trimethyl histone lysine 27 (H3K27me3) synthesis induced up to 40% of the latent HIV proviruses. In contrast, there was less than 5% induction of latent proviruses following knockdown of SUV39H1, which is required for H3K9me3 synthesis. Knockdown of EZH2 also sensitized latent proviruses to external stimuli, such as T-cell receptor stimulation, and slowed the reversion of reactivated proviruses to latency. Similarly, cell populations that responded poorly to external stimuli carried HIV proviruses that were enriched in H3K27me3 and relatively depleted in H3K9me3. Treating latently infected cells with the HKMT inhibitor 3-deazaneplanocin A, which targets EZH2, led to the reactivation of silenced proviruses, whereas chaetocin and BIX01294 showed only minimal reactivation activities. These findings suggest that PRC2-mediated silencing is an important feature of HIV latency and that inhibitors of histone methylation may play a useful role in induction strategies designed to eradicate latent HIV pools. 相似文献
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Athanasia Sepsa Georgia Levidou Antonis Gargalionis Christos Adamopoulos Anastasia Spyropoulou Georgia Dalagiorgou Irene Thymara Efstathios Boviatsis Marios S. Themistocleous Kalliopi Petraki George Vrettakos Vassilis Samaras Athanassios Zisakis Efstratios Patsouris Christina Piperi Penelope Korkolopoulou 《PloS one》2015,10(1)
Although epigenetic alterations play an essential role in gliomagenesis, the relevance of aberrant histone modifications and the respective enzymes has not been clarified. Experimental data implicates histone H3 lysine (K) methyltransferases SETDB1 and SUV39H1 into glioma pathobiology, whereas linker histone variant H1.0 and H4K20me3 reportedly affect prognosis. We investigated the expression of H3K9me3 and its methyltransferases along with H4K20me3 and H1x in 101 astrocytic tumors with regard to clinicopathological characteristics and survival. The effect of SUV39H1 inhibition by chaetocin on the proliferation, colony formation and migration of T98G cells was also examined. SETDB1 and cytoplasmic SUV39H1 levels increased from normal brain through low-grade to high-grade tumors, nuclear SUV39H1 correlating inversely with grade. H3K9me3 immunoreactivity was higher in normal brain showing no association with grade, whereas H1x and H4K20me3 expression was higher in grade 2 than in normal brain or high grades. These expression patterns of H1x, H4K20me3 and H3K9me3 were verified by Western immunoblotting. Chaetocin treatment significantly reduced proliferation, clonogenic potential and migratory ability of T98G cells. H1x was an independent favorable prognosticator in glioblastomas, this effect being validated in an independent set of 66 patients. Diminished nuclear SUV39H1 expression adversely affected survival in univariate analysis. In conclusion, H4K20me3 and H3K9 methyltransferases are differentially implicated in astroglial tumor progression. Deregulation of H1x emerges as a prognostic biomarker. 相似文献
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The HP1α–CAF1–SetDB1‐containing complex provides H3K9me1 for Suv39‐mediated K9me3 in pericentric heterochromatin
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Alejandra Loyola Tiziana Bonaldi Danièle Roche Jean Pierre Quivy Axel Imhof Yoshihiro Nakatani Sharon Y R Dent Geneviève Almouzni 《EMBO reports》2009,10(7):769-775
Trimethylation of lysine 9 in histone H3 (H3K9me3) enrichment is a characteristic of pericentric heterochromatin. The hypothesis of a stepwise mechanism to establish and maintain this mark during DNA replication suggests that newly synthesized histone H3 goes through an intermediate methylation state to become a substrate for the histone methyltransferase Suppressor of variegation 39 (Suv39H1/H2). How this intermediate methylation state is achieved and how it is targeted to the correct place at the right time is not yet known. Here, we show that the histone H3K9 methyltransferase SetDB1 associates with the specific heterochromatin protein 1α (HP1α)–chromatin assembly factor 1 (CAF1) chaperone complex. This complex monomethylates K9 on non‐nucleosomal histone H3. Therefore, the heterochromatic HP1α–CAF1–SetDB1 complex probably provides H3K9me1 for subsequent trimethylation by Suv39H1/H2 in pericentric regions. The connection of CAF1 with DNA replication, HP1α with heterochromatin formation and SetDB1 for H3K9me1 suggests a highly coordinated mechanism to ensure the propagation of H3K9me3 in pericentric heterochromatin during DNA replication. 相似文献
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HIV-1 latency represents a major problem in the eradication of HIV-1 in infected individuals treated with highly active anti-retroviral therapy. Histone deacetylase (HDAC) inhibits HIV-1 gene expression and virus production and may contribute to quiescence of HIV-1 within resting CD4+ T cells. Here, we evaluated the effect of Oxamflatin, a class I HDAC inhibitor, on the epigenetic change at HIV-1 long terminal repeat (LTR) and the induction of the latent viruses in the latency Jurkat T cell line. Flow cytometry assay showed that Oxamflatin activate HIV-1 gene expression in these latently infected cells by 2-17 fold than background levels. Chromatin immunoprecipitation (ChIP) assays further revealed that Oxamflatin increase the acetylation level of histone H3 and histone H4 at the nucleosome 1(nuc-1) site of the HIV-1 LTR compared to mock treatment. We also found that Oxamflatin had a synergization with prostratin, or 5-azacytidine or tumor necrosis factor-α to activate the HIV-1 promoter. Taken together, our results suggest that the histone acetylation plays an important role in regulating HIV-1 LTR gene expression, and Oxamflatin has potential as drug candidates as antilatency therapies. 相似文献