Role of CHD chromatin remodelers in heart development

Chromodomain helicase DNA-binding (CHD) proteins are ATP-dependent chromatin remodelers that regulate chromatin accessibility, genome organization, and lineage-specific transcription during embryonic development. There are nine members of this family of proteins. Increasing genetic and functional evidence links mutations in multiple CHD genes to congenital-heart disease, arrhythmias, and cardiomyopathies. However, the stage-specific contributions of individual CHD-family members to cardiac development and functional maturation remain incompletely defined.

This narrative review summarizes studies retrieved from the PubMed database that investigate CHD chromatin remodelers in heart development and cardiac disease, with an emphasis on genetic models, developmental analyses, and recent multi-omics approaches.

Available evidence indicates that distinct CHD-family members contribute to cardiac development with different levels of support across human genetics, in vivo models, and stem-cell systems. CHD7 has the strongest combined evidence base, including human syndromic genetics and mouse lineage-specific studies, supporting roles in enhancer accessibility, second-heart-field or neural-crest programs, outflow-tract morphogenesis, and later cardiomyocyte maturation. CHD3 and CHD4, as ATPase subunits of the nucleosome remodeling and deacetylase complex, are supported mainly by mouse developmental studies and emerging human genetic data indicating functions in chamber specification, maintenance of lineage boundary, and developmental gene silencing. For CHD8, direct cardiac evidence remains limited. Available data suggest roles in cardiomyocyte survival, ventricular growth, sarcomeric organization, and metabolic homeostasis, but several mechanistic interpretations are inferred from stem-cell or non-cardiac systems. Direct cardiac roles of CHD1, CHD2, CHD5, CHD6, and CHD9 remain poorly defined.

Current studies support a working model in which CHD remodelers shape enhancer activity, transcription-factor occupancy, and chromatin accessibility during cardiac morphogenesis and maturation. However, coordinated regulation across CHD-family members has not yet been directly established experimentally. Future progress will depend on integrative genetics, time-resolved multi-omics, and cardiac organoid/in vivo validation.