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Chromatin regulation by Brg1 underlies heart muscle development and disease

A Corrigendum to this article was published on 29 June 2011


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.

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Figure 1: Brg1 promotes myocardial proliferation.
Figure 2: Brg1 suppresses myocardial differentiation.
Figure 3: Brg1 is required for cardiac hypertrophy.
Figure 4: MHC regulation by Brg1, PARP and HDAC.
Figure 5: BRG1 activation in human cardiomyopathy.


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We thank B. Black for providing Mef2c-cre mice; G. R. Crabtree, D. Bernstein, M. Rabinovitch, R. Robbins, V. Christoffels, W. Shou, J. Wysocka and K. Zhao for materials and discussions; B. Wu, A. Sun, J. Lehrer-Graiwer, W. Li, C. Y. Lin and C. J. Lin for technical assistance; M. Zhao, M. Zeini and K. Stankunas for technical advice to H.-L.C., P.H. and C.T.H. C.-P.C. was supported by funds from the NIH, American Heart Association (AHA), Children’s Heart Foundation, March of Dimes Foundation, Office of the University of California, California Institute of Regenerative Medicine, Kaiser Foundation, Baxter Foundation, Oak Foundation, Stanford Cardiovascular Institute and W. Younger. C.T.H. was supported by predoctoral training fellowships from the NIH and AHA; H.-L.C. by a visiting scholar fellowship; C.S. by Kirschstein–NRSA Postdoctoral Fellowship; B.Z. by NIH and AHA grants.

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C.-P.C. and C.T.H. were responsible for the original concept and design of primary experiments. C.T.H conducted most experiments, defining the phenotypes and Brg1, Bmp and HDAC interactions. P.H., J.Y. and H.-L.C. contributed equally to this work, and the order of authorship does not reflect their relative contributions. P.H. defined PARP1 and Brg1 interactions and HDAC binding to Brg1 and MHC. J.Y. contributed to gene expression, hypertrophy and chromatin studies. H.-L.C. developed the TAC procedure and studied cardiac hypertrophy. C.S. generated mouse founders and purified antibodies. E.A. collected clinical heart tissues. B.Z. generated Tnnt2-rtTA;Tre-cre mice. C.T.H. and C.-P.C. prepared the manuscript with contributions from P.H., J.Y., H.-L.C., C.S., E.A. and B.Z.

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Correspondence to Ching-Pin Chang.

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Hang, C., Yang, J., Han, P. et al. Chromatin regulation by Brg1 underlies heart muscle development and disease. Nature 466, 62–67 (2010).

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