Chromatin remodelers in heart development and congenital heart defects

Abstract Congenital heart defects (CHDs) are one of the most common birth defects, affecting 0.8–1% of livebirths and ~ 10% of stillbirths. CHDs arise from perturbations during cardiogenesis, a highly coordinated process involving spatiotemporal gene expression, cell-fate decisions, morphogenesis, and patterning. These cellular and molecular processes are regulated by transcription and chromatin. Recent evidences highlight a critical role of chromatin-modifying proteins, especially ATP-dependent chromatin remodeling factors (or remodelers), to orchestrate cardiac gene expression programs. Chromatin remodelers use ATP hydrolysis as an energy source to reposition, eject, or restructure nucleosomes, thereby modulating access of transcriptional machinery to DNA. Mutations, deletions, or dysregulation of chromatin remodelers can disrupt normal cardiac development and have been increasingly associated with a spectrum of CHDs, in both animal models and human genetic studies. Here, we summarize the current understanding of ATP-dependent chromatin remodelers, including SWI/SNF, ISWI, CHD, and INO80 families in cardiac development. We discuss how their precise regulation is essential for proper cell lineage specification, morphogenesis, and structural integrity of the heart, and how their dysfunction contributes to CHDs. Insights into epigenetic mechanisms underlying CHD pathogenesis may open potential avenues for therapeutic interventions.