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EED通过与组蛋白去乙酰化酶（HDACs）相互作用对心脏成熟进行的调控不依赖于H3K27me3。

EED orchestration of heart maturation through interaction with HDACs is H3K27me3-independent.

作者信息

Ai Shanshan, Peng Yong, Li Chen, Gu Fei, Yu Xianhong, Yue Yanzhu, Ma Qing, Chen Jinghai, Lin Zhiqiang, Zhou Pingzhu, Xie Huafeng, Prendiville Terence W, Zheng Wen, Liu Yuli, Orkin Stuart H, Wang Da-Zhi, Yu Jia, Pu William T, He Aibin

机构信息

Institute of Molecular Medicine, Peking-Tsinghua Center for Life Sciences, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, China.

Department of Cardiology, Boston Children's Hospital, Boston, United States.

出版信息

Elife. 2017 Apr 10;6:e24570. doi: 10.7554/eLife.24570.

DOI:10.7554/eLife.24570
PMID:28394251
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5400508/
Abstract

In proliferating cells, where most Polycomb repressive complex 2 (PRC2) studies have been performed, gene repression is associated with PRC2 trimethylation of H3K27 (H3K27me3). However, it is uncertain whether PRC2 writing of H3K27me3 is mechanistically required for gene silencing. Here, we studied PRC2 function in postnatal mouse cardiomyocytes, where the paucity of cell division obviates bulk H3K27me3 rewriting after each cell cycle. EED (embryonic ectoderm development) inactivation in the postnatal heart (Eed) caused lethal dilated cardiomyopathy. Surprisingly, gene upregulation in Eed was not coupled with loss of H3K27me3. Rather, the activating histone mark H3K27ac increased. EED interacted with histone deacetylases (HDACs) and enhanced their catalytic activity. HDAC overexpression normalized Eed heart function and expression of derepressed genes. Our results uncovered a non-canonical, H3K27me3-independent EED repressive mechanism that is essential for normal heart function. Our results further illustrate that organ dysfunction due to epigenetic dysregulation can be corrected by epigenetic rewiring.

摘要

在增殖细胞中（大多数关于多梳抑制复合物2（PRC2）的研究都是在此类细胞中进行的），基因抑制与H3K27的PRC2三甲基化（H3K27me3）相关。然而，H3K27me3的PRC2写入在基因沉默的机制上是否是必需的尚不确定。在这里，我们研究了PRC2在出生后小鼠心肌细胞中的功能，在这些细胞中，细胞分裂很少，避免了每个细胞周期后大量H3K27me3的重写。出生后心脏中EED（胚胎外胚层发育）失活（Eed）导致致命的扩张型心肌病。令人惊讶的是，Eed中的基因上调与H3K27me3的缺失并不相关。相反，激活组蛋白标记H3K27ac增加。EED与组蛋白脱乙酰酶（HDAC）相互作用并增强其催化活性。HDAC的过表达使Eed心脏功能和去抑制基因的表达恢复正常。我们的结果揭示了一种非经典的、不依赖H3K27me3的EED抑制机制，该机制对正常心脏功能至关重要。我们的结果进一步表明，表观遗传失调导致的器官功能障碍可以通过表观遗传重塑来纠正。

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