| First Author | Stathopoulou A | Year | 2023 |
| Journal | Cardiovasc Res | PubMed ID | 37052590 |
| Mgi Jnum | J:338018 | Mgi Id | MGI:7509867 |
| Doi | 10.1093/cvr/cvad059 | Citation | Stathopoulou A, et al. (2023) CHARGE syndrome-associated CHD7 acts at ISL1-regulated enhancers to modulate second heart field gene expression. Cardiovasc Res |
| abstractText | AIMS: Haploinsufficiency 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 RESULTS: We 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 versus differentiating cardiomyocytes. CONCLUSION: We show that CHD7 interacts with ISL1, binds ISL1-regulated cardiac enhancers and modulates gene expression across the mesodermal heart fields during cardiac morphogenesis. TRANSLATIONAL PERSPECTIVE: CHD7 is a chromatin remodeller haploinsufficient in CHARGE syndrome and implicated in autism spectrum disorder and various cancers. Heart defects in the syndrome are recapitulated by murine loss-of-function in two linages, neural crest and cardiopharyngeal mesoderm (CPM). CHD7 regulates vital cardiogenic genes via binding predominantly to enhancers distant from the target gene at sites often shared with the pioneer transcription factor ISL1. CHD7 bound enhancer elements show highly dynamic switching of histone modifications during the mesodermal to cardiac progenitor cell transition. Thus, manipulation of CHD7 activity may assist in directed differentiation of distinct cardiovascular progenitors for use in regenerative/repair therapeutics. |
