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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Wang, Z; Zhang, X-J; Ji, Y-X; Zhang, P; Deng, K-Q; Gong, J; Ren, S; Wang, X; Chen, I; Wang, H; Gao, C; Yokota, T; Ang, YS; Li, S; Cass, A; Vondriska, TM; Li, G; Deb, A; Srivastava, D; Yang, H-T; Xiao, X; Li, H; Wang, Y

Published Date

  • October 2016

Published In

Volume / Issue

  • 22 / 10

Start / End Page

  • 1131 - 1139

PubMed ID

  • 27618650

Pubmed Central ID

  • PMC5053883

Electronic International Standard Serial Number (EISSN)

  • 1546-170X

Digital Object Identifier (DOI)

  • 10.1038/nm.4179

Language

  • eng

Conference Location

  • United States