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

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

Nature medicine (2016-09-13)
Zhihua Wang, Xiao-Jing Zhang, Yan-Xiao Ji, Peng Zhang, Ke-Qiong Deng, Jun Gong, Shuxun Ren, Xinghua Wang, Iris Chen, He Wang, Chen Gao, Tomohiro Yokota, Yen Sin Ang, Shen Li, Ashley Cass, Thomas M Vondriska, Guangping Li, Arjun Deb, Deepak Srivastava, Huang-Tian Yang, Xinshu Xiao, Hongliang Li, Yibin Wang
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.

MATERIALS
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Sigma-Aldrich
Anti-Puromycin Antibody, clone 12D10, clone 12D10, from mouse
Roche
DIG Northern Starter Kit, suitable for Northern blotting, sufficient for 10 labeling reactions