CHD4 is recruited by GATA4 and NKX2-5 to repress noncardiac gene programs in the developing heart.

Autor:	Robbe ZL; Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA., Shi W; Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA., Wasson LK; Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA., Scialdone AP; Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA., Wilczewski CM; Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.; McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA., Sheng X; Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA., Hepperla AJ; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA., Akerberg BN; Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts 02115, USA., Pu WT; Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts 02115, USA., Cristea IM; Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA., Davis IJ; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.; Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA., Conlon FL; Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.; McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Jazyk:	angličtina
Zdroj:	Genes & development [Genes Dev] 2022 Apr 01; Vol. 36 (7-8), pp. 468-482. Date of Electronic Publication: 2022 Apr 21.
DOI:	10.1101/gad.349154.121
Abstrakt:	The nucleosome remodeling and deacetylase (NuRD) complex is one of the central chromatin remodeling complexes that mediates gene repression. NuRD is essential for numerous developmental events, including heart development. Clinical and genetic studies have provided direct evidence for the role of chromodomain helicase DNA-binding protein 4 (CHD4), the catalytic component of NuRD, in congenital heart disease (CHD), including atrial and ventricular septal defects. Furthermore, it has been demonstrated that CHD4 is essential for mammalian cardiomyocyte formation and function. A key unresolved question is how CHD4/NuRD is localized to specific cardiac target genes, as neither CHD4 nor NuRD can directly bind DNA. Here, we coupled a bioinformatics-based approach with mass spectrometry analyses to demonstrate that CHD4 interacts with the core cardiac transcription factors GATA4, NKX2-5, and TBX5 during embryonic heart development. Using transcriptomics and genome-wide occupancy data, we characterized the genomic landscape of GATA4, NKX2-5, and TBX5 repression and defined the direct cardiac gene targets of the GATA4-CHD4, NKX2-5-CHD4, and TBX5-CHD4 complexes. These data were used to identify putative cis -regulatory elements controlled by these complexes. We genetically interrogated two of these silencers in vivo: Acta1 and Myh11 We show that deletion of these silencers leads to inappropriate skeletal and smooth muscle gene misexpression, respectively, in the embryonic heart. These results delineate how CHD4/NuRD is localized to specific cardiac loci and explicates how mutations in the broadly expressed CHD4 protein lead to cardiac-specific disease states. (© 2022 Robbe et al.; Published by Cold Spring Harbor Laboratory Press.)
Databáze:	MEDLINE
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