The long noncoding RNA Chaer defines an epigenetic checkpoint in cardiac hypertrophy

被引：384

作者：

Wang, Zhihua ^{[1
,2
,3
,4
]}

Zhang, Xiao-Jing ^{[1
,2
,3
]}

Ji, Yan-Xiao ^{[1
,2
,3
]}

Zhang, Peng ^{[1
,2
,3
]}

Deng, Ke-Qiong ^{[1
,2
,3
]}

Gong, Jun ^{[1
,2
,3
]}

Ren, Shuxun ^{[4
]}

Wang, Xinghua ^{[5
]}

Chen, Iris ^{[4
]}

Wang, He ^{[4
]}

Gao, Chen ^{[4
]}

Yokota, Tomohiro ^{[4
]}

Ang, Yen Sin ^{[6
,7
]}

Li, Shen ^{[8
,9
]}

Cass, Ashley ^{[10
,11
]}

Vondriska, Thomas M. ^{[4
]}

Li, Guangping ^{[5
]}

Deb, Arjun ^{[8
,9
]}

Srivastava, Deepak

Yang, Huang-Tian ^{[12
,13
,14
]}

Xiao, Xinshu ^{[10
,11
]}

Li, Hongliang ^{[1
,2
,3
]}

Wang, Yibin ^{[4
,8
,9
]}

机构：

[1] Wuhan Univ, Renmin Hosp, Dept Cardiol, Wuhan, Peoples R China

[2] Wuhan Univ, Anim Expt Ctr, Anim Biosafety Level Lab 3, Wuhan, Peoples R China

[3] Wuhan Univ, Med Res Inst, Sch Med, Wuhan, Peoples R China

[4] Univ Calif Los Angeles, David Geffen Sch Med, Dept Anesthesiol, Div Mol Med, Los Angeles, CA 90095 USA

[5] Tianjin Med Univ, Hosp 2, Tianjin Inst Cardiol, Dept Cardiol, Tianjin, Peoples R China

[6] Gladstone Inst Cardiovasc Dis, San Francisco, CA USA

[7] Univ Calif San Francisco, Sch Med, San Francisco, CA USA

[8] Univ Calif Los Angeles, David Geffen Sch Med, Cardiovasc Res Labs, Los Angeles, CA 90095 USA

[9] Univ Calif Los Angeles, David Geffen Sch Med, Cardiovasc Res Labs, Los Angeles, CA 90095 USA

[10] Univ Calif Los Angeles, David Geffen Sch Med, Inst Mol Biol, Dept Integrat Biol & Physiol,Coll Life Sci, Los Angeles, CA 90095 USA

[11] Univ Calif Los Angeles, Bioinformat Interdept Program, Los Angeles, CA USA

[12] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Hlth Sci, Key Lab Stem Cell Biol, Shanghai, Peoples R China

[13] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Hlth Sci, Lab Mol Cardiol, Shanghai, Peoples R China

[14] Shanghai Jiao Tong Univ, Sch Med, Shanghai, Peoples R China

来源：

NATURE MEDICINE | 2016年 / 22卷 / 10期

关键词：

HISTONE METHYLATION; GENE-EXPRESSION; HEART; BINDING; MTOR; RAPTOR; IDENTIFICATION; REPRESSION; REGULATOR; CHROMATIN;

D O I：

10.1038/nm.4179

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Epigenetic reprogramming is a critical process of pathological gene induction during cardiac hypertrophy and remodeling, but the underlying regulatory mechanisms remain to be elucidated. Here we identified a heart-enriched long noncoding (Inc)RNA, named cardiac-hypertrophy-associated epigenetic regulator (Chaer), which is necessary for the development of cardiac hypertrophy. Mechanistically, Chaer directly interacts with the catalytic subunit of polycomb repressor complex 2 (PRC2). This interaction, which is mediated by a 66-mer motif in Chaer, interferes with PRC2 targeting to genomic loci, thereby inhibiting histone H3 lysine 27 methylation at the promoter regions of genes involved in cardiac hypertrophy. The interaction between Chaer and PRC2 is transiently induced after hormone or stress stimulation in a process involving mammalian target of rapamycin complex 1, and this interaction is a prerequisite for epigenetic reprogramming and induction of genes involved in hypertrophy. Inhibition of Chaer expression in the heart before, but not after, the onset of pressure overload substantially attenuates cardiac hypertrophy and dysfunction. Our study reveals that stress-induced pathological gene activation in the heart requires a previously uncharacterized IncRNA-dependent epigenetic checkpoint.

引用

页码：1131 / 1139

页数：9

共 54 条

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