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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blotting, Northern
  • Cardiomegaly / genetics*
  • Cardiomegaly / metabolism
  • Chromatin Immunoprecipitation
  • Computer Simulation
  • Echocardiography
  • Epigenesis, Genetic / genetics*
  • Gene Expression Profiling
  • Gene Knockdown Techniques
  • Heart / diagnostic imaging*
  • Histone Code / genetics*
  • Humans
  • Immunoblotting
  • In Situ Hybridization, Fluorescence
  • In Vitro Techniques
  • Induced Pluripotent Stem Cells
  • Mechanistic Target of Rapamycin Complex 1
  • Methylation
  • Mice
  • Mice, Knockout
  • Multiprotein Complexes / metabolism
  • Myocardium / metabolism*
  • Myocytes, Cardiac / metabolism*
  • Polycomb Repressive Complex 2 / metabolism*
  • RNA, Long Noncoding / genetics*
  • Rats
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Multiprotein Complexes
  • RNA, Long Noncoding
  • Polycomb Repressive Complex 2
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1