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AimsHaploinsufficiency of the chromo-domain protein CHD7 underlies most cases of CHARGE syndrome, a multisystem birth defect including congenital heart malformation. Context specific roles for CHD7 in various stem, progenitor, and differentiated cell lineages have been reported. Previously, we showed severe defects when Chd7 is absent from cardiopharyngeal mesoderm (CPM). Here, we investigate altered gene expression in the CPM and identify specific CHD7-bound target genes with known roles in the morphogenesis of affected structures.Methods and resultsWe generated conditional KO of Chd7 in CPM and analysed cardiac progenitor cells using transcriptomic and epigenomic analyses, in vivo expression analysis, and bioinformatic comparisons with existing datasets. We show CHD7 is required for correct expression of several genes established as major players in cardiac development, especially within the second heart field (SHF). We identified CHD7 binding sites in cardiac progenitor cells and found strong association with histone marks suggestive of dynamically regulated enhancers during the mesodermal to cardiac progenitor transition of mESC differentiation. Moreover, CHD7 shares a subset of its target sites with ISL1, a pioneer transcription factor in the cardiogenic gene regulatory network, including one enhancer modulating Fgf10 expression in SHF progenitor cells vs. differentiating cardiomyocytes.ConclusionWe show that CHD7 interacts with ISL1, binds ISL1-regulated cardiac enhancers, and modulates gene expression across the mesodermal heart fields during cardiac morphogenesis.

Original publication

DOI

10.1093/cvr/cvad059

Type

Journal article

Journal

Cardiovascular research

Publication Date

09/2023

Volume

119

Pages

2089 - 2105

Addresses

Developmental Biology of Birth Defects, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.

Keywords

Heart, Myocytes, Cardiac, Humans, DNA Helicases, DNA-Binding Proteins, Gene Expression, Gene Expression Regulation, Developmental, Enhancer Elements, Genetic, CHARGE Syndrome