Epigenetic response to environmental stress: Assembly of BRG1-G9a/GLP-DNMT3 repressive chromatin complex on Myh6 promoter in pathologically stressed hearts.
Epigenetic response to environmental stress: Assembly of BRG1-G9a/GLP-DNMT3 repressive chromatin complex on Myh6 promoter in pathologically stressed hearts.
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DOI：
10.1016/j.bbamcr.2016.03.002
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发表时间：
2016-07
期刊：
影响因子：
--
通讯作者：
Chang CP
中科院分区：
文献类型：
--
作者：
Han P;Li W;Yang J;Shang C;Lin CH;Cheng W;Hang CT;Cheng HL;Chen CH;Wong J;Xiong Y;Zhao M;Drakos SG;Ghetti A;Li DY;Bernstein D;Chen HS;Quertermous T;Chang CP
染色质结构由核小体定位、组蛋白修饰和DNA甲基化决定。染色质修饰在病理条件下如何协调改变仍然是难以捉摸的。在这里，我们描述了一个协调的染色质修饰的心脏应激激活机制。在小鼠中，病理性应激激活心肌细胞表达Brg 1（核小体重塑因子）、G9 a/Glp（组蛋白甲基转移酶）和Dnmt 3（DNA甲基转移酶）。一旦激活，Brg 1招募G9 a，然后Dnmt 3顺序组装抑制性染色质-标记H3 K9和CpG甲基化-在一个关键的分子马达基因（Myh 6），从而沉默Myh 6和损害心脏收缩。Brg 1、G9 a或Dnmt 3的破坏可消除抑制性染色质标记并解除Myh 6的抑制，从而减少应激诱导的心功能障碍。在人类肥大心脏中，BRG 1-G9 a/GLP-DNMT 3复合物也被激活;其水平与H3 K9/CpG甲基化、Myh 6抑制和心肌病相关。我们的研究证明了应激心脏中染色质组装的新机制以及恢复Myh 6和心室功能的新治疗靶点。应激诱导的Brg 1-G9 a-Dnmt 3相互作用和Myh 6上的抑制性染色质组装序列说明了心脏表观遗传学响应环境信号的分子机制。这篇文章是由Marcus Schaub和Hughes Abriel编辑的题为：心肌细胞生物学：心脏中发育和环境线索的整合的特刊的一部分。
Chromatin structure is determined by nucleosome positioning, histone modifications, and DNA methylation. How chromatin modifications are coordinately altered under pathological conditions remains elusive. Here we describe a stress-activated mechanism of concerted chromatin modification in the heart. In mice, pathological stress activates cardiomyocytes to express Brg1 (nucleosome-remodeling factor), G9a/Glp (histone methyltransferase), and Dnmt3 (DNA methyltransferase). Once activated, Brg1 recruits G9a and then Dnmt3 to sequentially assemble repressive chromatin—marked by H3K9 and CpG methylation—on a key molecular motor gene (Myh6), thereby silencing Myh6 and impairing cardiac contraction. Disruption of Brg1, G9a or Dnmt3 erases repressive chromatin marks and de-represses Myh6, reducing stress-induced cardiac dysfunction. In human hypertrophic hearts, BRG1–G9a/GLP–DNMT3 complex is also activated; its level correlates with H3K9/CpG methylation, Myh6 repression, and cardiomyopathy. Our studies demonstrate a new mechanism of chromatin assembly in stressed hearts and novel therapeutic targets for restoring Myh6 and ventricular function. The stress-induced Brg1–G9a–Dnmt3 interactions and sequence of repressive chromatin assembly on Myh6 illustrates a molecular mechanism by which the heart epigenetically responds to environmental signals. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.
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