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Nat Med. 2016 Oct;22(10):1131-1139. doi: 10.1038/nm.4179. Epub 2016 Sep 12.

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

Wang Z1,2,3,4, Zhang XJ1,2,3, Ji YX1,2,3, Zhang P1,2,3, Deng KQ1,2,3, Gong J1,2,3, Ren S4, Wang X5, Chen I4, Wang H4, Gao C4, Yokota T4, Ang YS6,7, Li S8,9, Cass A10,11, Vondriska TM4, Li G5, Deb A8,9, Srivastava D6,7, Yang HT12,13,14, Xiao X10,11, Li H1,2,3, Wang Y4,8,9.

Author information

1
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
2
Animal Experiment Center-Animal Biosafety Level 3 Laboratory, Wuhan University, Wuhan, China.
3
Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
4
Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine, University of California at Los Angeles (UCLA), Los Angeles, California, USA.
5
Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China.
6
Gladstone Institute of Cardiovascular Diseases, San Francisco, California, USA.
7
University of California, San Francisco, School of Medicine, San Francisco, California, USA.
8
Department of Medicine, Cardiology Division, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
9
Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
10
Department of Integrative Biology and Physiology, College of Life Sciences, Molecular Biology Institute, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
11
Bioinformatics Interdepartmental Program, University of California at Los Angeles, Los Angeles, California, USA.
12
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
13
Laboratory of Molecular Cardiology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
14
Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Abstract

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 (lnc)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 lncRNA-dependent epigenetic checkpoint.

PMID:
27618650
PMCID:
PMC5053883
DOI:
10.1038/nm.4179
[Indexed for MEDLINE]
Free PMC Article

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