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 and Ching-Pin Chang ()
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Calvin T. Hang: Stanford University School of Medicine, Stanford, California 94305, USA
Jin Yang: Stanford University School of Medicine, Stanford, California 94305, USA
Pei Han: Stanford University School of Medicine, Stanford, California 94305, USA
Hsiu-Ling Cheng: Stanford University School of Medicine, Stanford, California 94305, USA
Ching Shang: Stanford University School of Medicine, Stanford, California 94305, USA
Euan Ashley: Stanford University School of Medicine, Stanford, California 94305, USA
Bin Zhou: Albert Einstein College of Medicine, Pediatrics and Medicine, Bronx, New York 10461, USA
Ching-Pin Chang: Stanford University School of Medicine, Stanford, California 94305, USA

Nature, 2010, vol. 466, issue 7302, 62-67

Abstract: 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 factors—Brg1, HDAC and PARP—cooperate to control developmental and pathological gene expression.

Date: 2010
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DOI: 10.1038/nature09130

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