Six methyltransferases divide labor in establishing genomic profiles of histone H3 lysine 9 methylation (H3K9me), an epigenomic modification controlling constitutive heterochromatin, gene repression, and silencing of retroelements. Among them, SETDB1 is recruited to active chromatin domains to silence the expression of endogenous retroviruses. In the context of experiments aimed at determining the impact of SETDB1 on stimulus-inducible gene expression in macrophages, we found that loss of H3K9me3 caused by SETDB1 depletion was associated with increased recruitment of CTCF to >1600 DNA binding motifs contained within SINE B2 repeats, a previously unidentified target of SETDB1-mediated repression. CTCF is an essential regulator of chromatin folding that restrains DNA looping by cohesin, thus creating boundaries among adjacent topological domains. Increased CTCF binding to SINE B2 repeats enhanced insulation at hundreds of sites and increased loop formation within topological domains containing lipopolysaccharide-inducible genes, which correlated with their impaired regulation in response to stimulation. These data indicate a role of H3K9me3 in restraining genomic distribution and activity of CTCF, with an impact on chromatin organization and gene regulation.

中文翻译：

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活性染色质中的 H3K9 三甲基化限制了 SINE B2 重复序列中功能性 CTCF 位点的使用

六种甲基转移酶分工建立组蛋白 H3 赖氨酸 9 甲基化 (H3K9me) 的基因组谱，这是一种控制组成型异染色质、基因抑制和逆转录元件沉默的表观基因组修饰。其中，SETDB1 被招募到活跃的染色质结构域以沉默内源性逆转录病毒的表达。在旨在确定 SETDB1 对巨噬细胞中刺激诱导基因表达影响的实验的背景下，我们发现由 SETDB1 耗尽引起的 H3K9me3 缺失与 CTCF 募集到 SINE B2 重复中包含的 >1600 个 DNA 结合基序的增加有关，一个以前未知的 SETDB1 介导的抑制目标。CTCF 是染色质折叠的重要调节剂，可通过黏附素抑制 DNA 环化，从而在相邻拓扑结构域之间形成边界。增加 CTCF 与 SINE B2 的结合可增强数百个位点的绝缘性，并增加含有脂多糖诱导基因的拓扑结构域内的环形成，这与它们对刺激反应的调节受损有关。这些数据表明 H3K9me3 在抑制 CTCF 基因组分布和活性方面的作用，对染色质组织和基因调控有影响。