Chromatin regulation by Brg1 underlies heart muscle development and disease

Calvin T. Hang, Jin Yang, Pei Han, Hsiu Ling Cheng, Ching Shang, Euan Ashley, Bin Zhou, Ching Pin Chang

Research output: Contribution to journalArticle

298 Scopus citations

Abstract

Cardiac hypertrophy and failure are characterized by transcriptional reprogramming of gene expression. Adult cardiomyocytes in mice primarily express α-myosin heavy chain (α-MHC, also known as Myh6), whereas embryonic cardiomyocytes express Β-MHC (also known as Myh7). Cardiac stress triggers adult hearts to undergo hypertrophy and a shift from α-MHC to fetal Β-MHC expression. Here we show that Brg1, a chromatin-remodelling protein, has a critical role in regulating cardiac growth, differentiation and gene expression. In embryos, Brg1 promotes myocyte proliferation by maintaining Bmp10 and suppressing p57kip2 expression. It preserves fetal cardiac differentiation by interacting with histone deacetylase (HDAC) and poly (ADP ribose) polymerase (PARP) to repress α-MHC and activate Β-MHC. In adults, Brg1 (also known as Smarca4) is turned off in cardiomyocytes. It is reactivated by cardiac stresses and forms a complex with its embryonic partners, HDAC and PARP, to induce a pathological α-MHC to Β-MHC shift. Preventing Brg1 re-expression decreases hypertrophy and reverses this MHC switch. BRG1 is activated in certain patients with hypertrophic cardiomyopathy, its level correlating with disease severity and MHC changes. Our studies show that Brg1 maintains cardiomyocytes in an embryonic state, and demonstrate an epigenetic mechanism by which three classes of chromatin-modifying factorsBrg1, HDAC and PARPcooperate to control developmental and pathological gene expression.

Original languageEnglish (US)
Pages (from-to)62-67
Number of pages6
JournalNature
Volume466
Issue number7302
DOIs
StatePublished - Jul 1 2010

ASJC Scopus subject areas

  • General

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