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

TitleCHD4 is recruited by GATA4 and NKX2-5 to repress noncardiac gene programs in the developing heart.
Publication TypeJournal Article
Year of Publication2022
AuthorsRobbe, ZL, Shi, W, Wasson, LK, Scialdone, AP, Wilczewski, CM, Sheng, X, Hepperla, AJ, Akerberg, BN, Pu, WT, Cristea, IM, Davis, IJ, Conlon, FL
JournalGenes Dev
Volume36
Issue7-8
Pagination468-482
Date Published2022 Apr 01
ISSN1549-5477
KeywordsAnimals, DNA Helicases, Genes, Homeobox, Mammals, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Myocytes, Cardiac, Nucleosomes, Transcription Factors
Abstract

<p>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 -regulatory elements controlled by these complexes. We genetically interrogated two of these silencers in vivo: and 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.</p>

DOI10.1101/gad.349154.121
Alternate JournalGenes Dev
PubMed ID35450884
PubMed Central IDPMC9067406
Grant ListR01 HD089275 / HD / NICHD NIH HHS / United States
R01 HL156424 / HL / NHLBI NIH HHS / United States