Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Chromatin regulation by Brg1 underlies heart muscle development and disease

A Corrigendum to this article was published on 29 June 2011

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 1

    van Rooij, E. et al. Control of stress-dependent cardiac growth and gene expression by a microRNA. Science 316, 575–579 (2007)

    ADS  CAS  Article  Google Scholar 

  2. 2

    Herron, T. J. & McDonald, K. S. Small amounts of α-myosin heavy chain isoform expression significantly increase power output of rat cardiac myocyte fragments. Circ. Res. 90, 1150–1152 (2002)

    CAS  Article  Google Scholar 

  3. 3

    Krenz, M. & Robbins, J. Impact of β-myosin heavy chain expression on cardiac function during stress. J. Am. Coll. Cardiol. 44, 2390–2397 (2004)

    CAS  Article  Google Scholar 

  4. 4

    James, J. et al. Forced expression of α-myosin heavy chain in the rabbit ventricle results in cardioprotection under cardiomyopathic conditions. Circulation 111, 2339–2346 (2005)

    CAS  Article  Google Scholar 

  5. 5

    Miyata, S., Minobe, W., Bristow, M. R. & Leinwand, L. A. Myosin heavy chain isoform expression in the failing and nonfailing human heart. Circ. Res. 86, 386–390 (2000)

    CAS  Article  Google Scholar 

  6. 6

    Abraham, W. T. et al. Coordinate changes in myosin heavy chain isoform gene expression are selectively associated with alterations in dilated cardiomyopathy phenotype. Mol. Med. 8, 750–760 (2002)

    CAS  Article  Google Scholar 

  7. 7

    Lowes, B. D. et al. Myocardial gene expression in dilated cardiomyopathy treated with β-blocking agents. N. Engl. J. Med. 346, 1357–1365 (2002)

    CAS  Article  Google Scholar 

  8. 8

    Blaxall, B. C., Tschannen-Moran, B. M., Milano, C. A. & Koch, W. J. Differential gene expression and genomic patient stratification following left ventricular assist device support. J. Am. Coll. Cardiol. 41, 1096–1106 (2003)

    CAS  Article  Google Scholar 

  9. 9

    Geisterfer-Lowrance, A. A. et al. A mouse model of familial hypertrophic cardiomyopathy. Science 272, 731–734 (1996)

    ADS  CAS  Article  Google Scholar 

  10. 10

    Schmitt, J. P. et al. Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function. Proc. Natl Acad. Sci. USA 103, 14525–14530 (2006)

    ADS  CAS  Article  Google Scholar 

  11. 11

    Lowes, B. D. et al. Changes in gene expression in the intact human heart. Downregulation of α-myosin heavy chain in hypertrophied, failing ventricular myocardium. J. Clin. Invest. 100, 2315–2324 (1997)

    CAS  Article  Google Scholar 

  12. 12

    McKinsey, T. A. & Olson, E. N. Toward transcriptional therapies for the failing heart: chemical screens to modulate genes. J. Clin. Invest. 115, 538–546 (2005)

    CAS  Article  Google Scholar 

  13. 13

    Ho, L. & Crabtree, G. R. Chromatin remodelling during development. Nature 463, 474–484 (2010)

    ADS  CAS  Article  Google Scholar 

  14. 14

    Bultman, S. et al. A Brg1 null mutation in the mouse reveals functional differences among mammalian SWI/SNF complexes. Mol. Cell 6, 1287–1295 (2000)

    CAS  Article  Google Scholar 

  15. 15

    Backs, J. & Olson, E. N. Control of cardiac growth by histone acetylation/deacetylation. Circ. Res. 98, 15–24 (2006)

    CAS  Article  Google Scholar 

  16. 16

    Schreiber, V., Dantzer, F., Ame, J. C. & de Murcia, G. Poly(ADP-ribose): novel functions for an old molecule. Nature Rev. Mol. Cell Biol. 7, 517–528 (2006)

    CAS  Article  Google Scholar 

  17. 17

    Bartha, E. et al. PARP inhibition delays transition of hypertensive cardiopathy to heart failure in spontaneously hypertensive rats. Cardiovasc. Res. 83, 501–510 (2009)

    ADS  CAS  Article  Google Scholar 

  18. 18

    Kong, Y. et al. Suppression of class I and II histone deacetylases blunts pressure-overload cardiac hypertrophy. Circulation 113, 2579–2588 (2006)

    CAS  Article  Google Scholar 

  19. 19

    Antos, C. L. et al. Dose-dependent blockade to cardiomyocyte hypertrophy by histone deacetylase inhibitors. J. Biol. Chem. 278, 28930–28937 (2003)

    CAS  Article  Google Scholar 

  20. 20

    Trivedi, C. M. et al. Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activity. Nature Med. 13, 324–331 (2007)

    CAS  Article  Google Scholar 

  21. 21

    Kee, H. J. et al. Inhibition of histone deacetylation blocks cardiac hypertrophy induced by angiotensin II infusion and aortic banding. Circulation 113, 51–59 (2006)

    CAS  Article  Google Scholar 

  22. 22

    Pillai, J. B. et al. Poly(ADP-ribose) polymerase-1-deficient mice are protected from angiotensin II-induced cardiac hypertrophy. Am. J. Physiol. Heart Circ. Physiol. 291, H1545–H1553 (2006)

    CAS  Article  Google Scholar 

  23. 23

    Stankunas, K. et al. Endocardial Brg1 represses ADAMTS1 to maintain the microenvironment for myocardial morphogenesis. Dev. Cell 14, 298–311 (2008)

    CAS  Article  Google Scholar 

  24. 24

    Sumi-Ichinose, C., Ichinose, H., Metzger, D. & Chambon, P. SNF2β-BRG1 is essential for the viability of F9 murine embryonal carcinoma cells. Mol. Cell. Biol. 17, 5976–5986 (1997)

    CAS  Article  Google Scholar 

  25. 25

    Chen, H. et al. BMP10 is essential for maintaining cardiac growth during murine cardiogenesis. Development 131, 2219–2231 (2004)

    CAS  Article  Google Scholar 

  26. 26

    Chang, C. P. et al. A field of myocardial-endocardial NFAT signaling underlies heart valve morphogenesis. Cell 118, 649–663 (2004)

    CAS  Article  Google Scholar 

  27. 27

    Verzi, M. P., McCulley, D. J., De Val, S., Dodou, E. & Black, B. L. The right ventricle, outflow tract, and ventricular septum comprise a restricted expression domain within the secondary/anterior heart field. Dev. Biol. 287, 134–145 (2005)

    CAS  Article  Google Scholar 

  28. 28

    Pandya, K. et al. Discordant on/off switching of gene expression in myocytes during cardiac hypertrophy in vivo. Proc. Natl Acad. Sci. USA 105, 13063–13068 (2008)

    ADS  CAS  Article  Google Scholar 

  29. 29

    Liu, R. et al. Regulation of CSF1 promoter by the SWI/SNF-like BAF complex. Cell 106, 309–318 (2001)

    CAS  Article  Google Scholar 

  30. 30

    Muchardt, C. & Yaniv, M. A human homologue of Saccharomyces cerevisiae SNF2/SWI2 and Drosophila brm genes potentiates transcriptional activation by the glucocorticoid receptor. EMBO J. 12, 4279–4290 (1993)

    CAS  Article  Google Scholar 

  31. 31

    Wu, B. et al. Inducible cardiomyocyte-specific gene disruption directed by the rat Tnnt2 promoter in the mouse. Genesis 48, 63–72 (2009)

    Google Scholar 

  32. 32

    Szabo, G. et al. Poly(ADP-Ribose) polymerase inhibition reduces reperfusion injury after heart transplantation. Circ. Res. 90, 100–106 (2002)

    CAS  Article  Google Scholar 

  33. 33

    Wang, Z. et al. Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell 138, 1019–1031 (2009)

    CAS  Article  Google Scholar 

  34. 34

    Morrow, A. G. & Brockenbrough, E. C. Surgical treatment of idiopathic hypertrophic subaortic stenosis: technic and hemodynamic results of subaortic ventriculomyotomy. Ann. Surg. 154, 181–189 (1961)

    CAS  Article  Google Scholar 

  35. 35

    Braunwald, E. Heart Disease: A Textbook of Cardiovascular Medicine (W.B. Saunders Company, 1997)

    Google Scholar 

  36. 36

    Kinugawa, K. et al. Regulation of thyroid hormone receptor isoforms in physiological and pathological cardiac hypertrophy. Circ. Res. 89, 591–598 (2001)

    CAS  Article  Google Scholar 

  37. 37

    Molkentin, J. D. et al. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93, 215–228 (1998)

    CAS  Article  Google Scholar 

  38. 38

    Boucher, P., Gotthardt, M., Li, W. P., Anderson, R. G. & Herz, J. LRP: role in vascular wall integrity and protection from atherosclerosis. Science 300, 329–332 (2003)

    ADS  CAS  Article  Google Scholar 

  39. 39

    Chang, C. P., Chen, L. & Crabtree, G. R. Sonographic staging of the developmental status of mouse embryos in utero. Genesis 36, 7–11 (2003)

    Article  Google Scholar 

Download references

Acknowledgements

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.

Author information

Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Ching-Pin Chang.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Text, Supplementary Figures 1-12 with legends and References. (PDF 15441 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hang, C., Yang, J., Han, P. et al. Chromatin regulation by Brg1 underlies heart muscle development and disease. Nature 466, 62–67 (2010). https://doi.org/10.1038/nature09130

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links