CHD4 AND THE NURD COMPLEX ORCHESTRATE A TRANSCRIPTIONAL NETWORK TO CONTROL CARDIAC SARCOMERE FORMATION Public Deposited

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  • March 19, 2019
Creator
  • Wilczewski, Caralynn
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • Cardiac development relies on proper cardiomyocyte differentiation, including expression and assembly of cell-type specific actomyosin subunits into a functional cardiac sarcomere. Control of this process involves not only promoting expression of cardiac sarcomere subunits but also repressing expression of non-cardiac myofibril paralogs. This level of transcriptional control requires broadly expressed multiprotein machines that modify and remodel the chromatin landscape to restrict transcription machinery access. Prominent among these is the Nucleosome Remodeling and Deacetylase (NuRD) complex, which includes the catalytic core subunit CHD4. Here, we demonstrate that direct CHD4-mediated repression of skeletal and smooth muscle myofibril isoforms is required for normal cardiac sarcomere formation, function, and embryonic survival early in gestation. Through transcriptomic and genome-wide analyses of CHD4 localization, we identified novel CHD4 binding sites in smooth muscle myosin heavy chain, fast skeletal α-actin, and the fast skeletal troponin complex genes. We further demonstrate that in the absence of CHD4, cardiomyocytes in the developing heart form a hybrid muscle cell that contains cardiac, skeletal and smooth muscle myofibril components. These misexpressed paralogs intercalate into the nascent cardiac sarcomere to disrupt sarcomere formation and cause impaired cardiac function in utero. We further identify two new binding partners of CHD4, GATA4 and NKX2-5, which are predicted to recruit the NuRD complex to these regulatory loci to mediate non-cardiac myofibril isoform repression in cardiomyocytes. These results demonstrate the genomic and physiological requirements for CHD4 in mammalian cardiac development and cardiomyocyte differentiation.
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Rights statement
  • In Copyright
Advisor
  • Conlon, Frank
  • Wade, Paul
  • Strahl, Brian
  • Qian, Li
  • Williams, Scott
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2018
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