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Proc Natl Acad Sci U S A. 2018 Jun 26;115(26):6727-6732. doi: 10.1073/pnas.1722219115. Epub 2018 Jun 11.

CHD4 and the NuRD complex directly control cardiac sarcomere formation.

Author information

1
Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
2
University of North Carolina McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
3
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
4
Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Durham, NC 27709.
5
Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
6
Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
7
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
8
University of North Carolina McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; frank_conlon@med.unc.edu.

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 noncardiac 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 unique 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. These results demonstrate the genomic and physiological requirements for CHD4 in mammalian cardiac development.

KEYWORDS:

chromatin; congenital heart disease; heart; nucleosome remodeling and deacetylase complex; sarcomere

PMID:
29891665
PMCID:
PMC6042121
DOI:
10.1073/pnas.1722219115
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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