Cardiac-enriched BAF chromatin-remodeling complex subunit Baf60c regulates gene expression programs essential for heart development and function

Xin Sun; Swetansu K Hota; Yu-Qing Zhou; Stefanie Novak; Dario Miguel-Perez; Danos Christodoulou; Christine E Seidman; J G Seidman; Carol C Gregorio; R Mark Henkelman; Janet Rossant; Benoit G Bruneau

doi:10.1242/bio.029512

Cardiac-enriched BAF chromatin-remodeling complex subunit Baf60c regulates gene expression programs essential for heart development and function

Biol Open. 2018 Jan 5;7(1):bio029512. doi: 10.1242/bio.029512.

Authors

Xin Sun^{1

2}, Swetansu K Hota^{3

4}, Yu-Qing Zhou⁵, Stefanie Novak⁶, Dario Miguel-Perez^{3

4}, Danos Christodoulou⁷, Christine E Seidman^{7

8}, J G Seidman⁷, Carol C Gregorio⁶, R Mark Henkelman^{5

9}, Janet Rossant^{1

2}, Benoit G Bruneau^{10

4

11

12}

Affiliations

¹ Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, M5G 1X8 Canada.
² Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8 Canada.
³ Gladstone Institutes, San Francisco, CA, 94158 USA.
⁴ Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, Gladstone Institutes, San Francisco, CA 94158, USA.
⁵ The Mouse Imaging Centre, The Hospital for Sick Children, Toronto, ON, M5G 1X8 Canada.
⁶ Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA.
⁷ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
⁸ Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁹ Department of Medical Biophysics, University of Toronto, Toronto, ON M5S 1A8 Canada.
¹⁰ Gladstone Institutes, San Francisco, CA, 94158 USA benoit.bruneau@gladstone.ucsf.edu.
¹¹ Department of Pediatrics, University of California, San Francisco, CA 94143, USA.
¹² Cardiovascular Research Institute, University of California, San Francisco, CA 94158, USA.

Abstract

How chromatin-remodeling complexes modulate gene networks to control organ-specific properties is not well understood. For example, Baf60c (Smarcd3) encodes a cardiac-enriched subunit of the SWI/SNF-like BAF chromatin complex, but its role in heart development is not fully understood. We found that constitutive loss of Baf60c leads to embryonic cardiac hypoplasia and pronounced cardiac dysfunction. Conditional deletion of Baf60c in cardiomyocytes resulted in postnatal dilated cardiomyopathy with impaired contractile function. Baf60c regulates a gene expression program that includes genes encoding contractile proteins, modulators of sarcomere function, and cardiac metabolic genes. Many of the genes deregulated in Baf60c null embryos are targets of the MEF2/SRF co-factor Myocardin (MYOCD). In a yeast two-hybrid screen, we identified MYOCD as a BAF60c interacting factor; we showed that BAF60c and MYOCD directly and functionally interact. We conclude that Baf60c is essential for coordinating a program of gene expression that regulates the fundamental functional properties of cardiomyocytes.

Keywords: Chromatin remodeling; Embryo; Gene regulation; Heart.

Abstract

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