In eukaryotic cells, the gene expression status is strictly controlled by epigenetic modifications on chromatin. The repressive status of chromatin largely contributes to HIV latency. Studies have shown that modification of histone H3K27 acts as a key molecular switch for activation or suppression of many cellular genes. In this study, we found that K27-acetylated histone H3 specifically recruited Super Elongation Complex (SEC), the transcriptional elongation complex essential for HIV-1 long terminal repeat (LTR)-mediated and general cellular transcription. Interestingly, H3K27 acetylation further stimulates H3R26 methylation, which subsequently abrogates the recruitment of SEC, forming a negative feedback regulatory loop. Importantly, by inhibiting methyltransferase activity of CARM1, the enzyme responsible for H3R26 methylation, HIV-1 transcription is reactivated in several HIV latency cell models, including a primary resting CD4+ T cell model. When combined with other latency disrupting compounds such as JQ1 or vorinostat/SAHA, the CARM1 inhibitor achieved synergistic effects on HIV-1 activation. This study suggests that coordinated and dynamic modifications at histone H3K27 and H3R26 orchestrate HIV-1 LTR-mediated transcription, and potentially opens a new avenue to disrupt latent HIV-1 infection by targeting specific epigenetic enzymes.

中文翻译：

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组蛋白修饰之间的串扰表明抑制精氨酸甲基转移酶CARM1活性可逆转HIV潜伏期

在真核细胞中，基因表达状态受到染色质表观遗传修饰的严格控制。染色质的抑制状态在很大程度上导致了HIV潜伏期。研究表明，组蛋白H3K27的修饰是激活或抑制许多细胞基因的关键分子开关。在这项研究中，我们发现K27-乙酰化的组蛋白H3专门募集了Super Elongation Complex（SEC），这是HIV-1长末端重复（LTR）介导的和一般的细胞转录所必需的转录伸长复合物。有趣的是，H3K27乙酰化进一步刺激了H3R26甲基化，随后取消了SEC的募集，从而形成了负反馈调节回路。重要的是，通过抑制负责H3R26甲基化的酶CARM1的甲基转移酶活性，HIV-1转录在几种HIV潜伏期细胞模型（包括主要的静息CD4 + T细胞模型）中被重新激活。当与其他干扰潜伏期的化合物（如JQ1或伏立诺他/ SAHA）组合使用时，CARM1抑制剂可对HIV-1激活产生协同作用。这项研究表明，在组蛋白H3K27和H3R26上的协调和动态修饰可以协调HIV-1 LTR介导的转录，并可能通过靶向特定的表观遗传酶为破坏潜在的HIV-1感染开辟一条新途径。