The long noncoding RNA Chaer defines an epigenetic checkpoint in cardiac hypertrophy.
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.
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|Animal Experiment Center-Animal Biosafety Level 3 Laboratory, Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.|Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine, University of California at Los Angeles (UCLA), Los Angeles, California, USA.
Zhihua
Z
Wang
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|Animal Experiment Center-Animal Biosafety Level 3 Laboratory, Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
Xiao-Jing
XJ
Zhang
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|Animal Experiment Center-Animal Biosafety Level 3 Laboratory, Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
Yan-Xiao
YX
Ji
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|Animal Experiment Center-Animal Biosafety Level 3 Laboratory, Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
Peng
P
Zhang
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|Animal Experiment Center-Animal Biosafety Level 3 Laboratory, Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
Ke-Qiong
KQ
Deng
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|Animal Experiment Center-Animal Biosafety Level 3 Laboratory, Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
Jun
J
Gong
Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine, University of California at Los Angeles (UCLA), Los Angeles, California, USA.
Shuxun
S
Ren
Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China.
Xinghua
X
Wang
Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine, University of California at Los Angeles (UCLA), Los Angeles, California, USA.
Iris
I
Chen
Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine, University of California at Los Angeles (UCLA), Los Angeles, California, USA.
He
H
Wang
Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine, University of California at Los Angeles (UCLA), Los Angeles, California, USA.
Chen
C
Gao
Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine, University of California at Los Angeles (UCLA), Los Angeles, California, USA.
Tomohiro
T
Yokota
Gladstone Institute of Cardiovascular Diseases, San Francisco, California, USA.|University of California, San Francisco, School of Medicine, San Francisco, California, USA.
Yen Sin
YS
Ang
Department of Medicine, Cardiology Division, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.|Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
Shen
S
Li
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.|Bioinformatics Interdepartmental Program, University of California at Los Angeles, Los Angeles, California, USA.
Ashley
A
Cass
Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine, University of California at Los Angeles (UCLA), Los Angeles, California, USA.
Thomas M
TM
Vondriska
Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China.
Guangping
G
Li
Department of Medicine, Cardiology Division, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.|Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
Arjun
A
Deb
Gladstone Institute of Cardiovascular Diseases, San Francisco, California, USA.|University of California, San Francisco, School of Medicine, San Francisco, California, USA.
Deepak
D
Srivastava
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|Laboratory of Molecular Cardiology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Huang-Tian
HT
Yang
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.|Bioinformatics Interdepartmental Program, University of California at Los Angeles, Los Angeles, California, USA.
Xinshu
X
Xiao
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.|Animal Experiment Center-Animal Biosafety Level 3 Laboratory, Wuhan University, Wuhan, China.|Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
Hongliang
H
Li
Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine, University of California at Los Angeles (UCLA), Los Angeles, California, USA.|Department of Medicine, Cardiology Division, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.|Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
Yibin
Y
Wang
D000818:Animals; D015152:Blotting, Northern; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D003198:Computer Simulation; D004452:Echocardiography; D044127:Epigenesis, Genetic / Q000235:genetics*; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006321:Heart / Q000000981:diagnostic imaging*; D042421:Histone Code / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D017404:In Situ Hybridization, Fluorescence; D066298:In Vitro Techniques; D057026:Induced Pluripotent Stem Cells; D000076222:Mechanistic Target of Rapamycin Complex 1; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000235:genetics*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D046912:Multiprotein Complexes; D062085:RNA, Long Noncoding; D063151:Polycomb Repressive Complex 2; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases