Journal
NATURE MEDICINE
Volume 22, Issue 10, Pages 1131-1139Publisher
NATURE PORTFOLIO
DOI: 10.1038/nm.4179
Keywords
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Funding
- US National Institute of Health (NIH) [HL070079, HL103205, HL108186, HL110667, HL115238, R01HG006264, U01HG007013]
- University of California at Los Angeles CTSI-Cardiovascular Pilot Team research grant [UL1TR000124]
- National Science Fund for Distinguished Young Scholars [81425005]
- Key Project of the National Natural Science Foundation [81330005, 81630011]
- National Science and Technology Support Project [2013YQ030923-05, 2014BAI02B01, 2015BAI08801]
- American Heart Association Western States Affiliate Postdoctoral Fellowship [15POST24970034]
- UCLA Eli and Edythe Broad Center Predoctoral Fellowship in Stem Cell Science
- China Scholarship Council [201406280042]
- Jennifer S. Buchwald Graduate Fellowship in Physiology
- NIH [T90DE022734]
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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 (Inc)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 IncRNA-dependent epigenetic checkpoint.
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