Gene Regulatory Networks in Postnatal Cardiomyocyte Maturation

Mammalian hearts must transition from fetal to postnatal states to achieve sustained contractility, necessitating cardiomyocyte (CM) maturation. This maturation involves developing specialized contractile units, expressing adult cardiac genes, arresting the cell cycle, and switching metabolism from glycolysis to oxidative phosphorylation. CM immaturity can lead to heart failure, a leading cause of mortality worldwide. Moreover, human pluripotent stem cell (PSC)-derived CMs exhibit immature, fetal-like phenotypes, limiting their potential in cardiac regenerative medicine. The molecular mechanisms underlying CM maturation are not well understood, although phenotypic changes associated with altered gene expression suggest a key role in transcriptional regulation. Chromatin-remodeling complexes, such as the Nucleosome Remodeling and Deacetylase (NuRD) complex, modify the chromatin landscape to ensure proper cardiac gene expression. We identified the chromodomain helicase DNA-binding protein 4 (CHD4), the core catalytic enzyme in the NuRD complex, as essential for CM formation in embryonic hearts. Mutations in CHD4 are associated with CM immaturity in congenital heart disease. However, the mechanism by which CHD4 regulates CM maturation remains unknown. Our central hypothesis is that CHD4 promotes CM maturation in postnatal hearts through distinct transcriptional programs different from those in embryonic hearts. Our preliminary data indicate that cardiac-specific manipulation of Chd4 in neonatal mice disrupts hallmark genes of CM maturation, CM contraction, and calcium handling. We also found that CHD4 interacts with the transcription factor Nuclear Factor I A (NFIA) and binds to different gene loci in postnatal versus embryonic CMs. We will (Aim 1) establish CHD4's requirement in CM maturation, (Aim 2) delineate how the CHD4/NuRD complex targets cardiac gene loci in postnatal CMs, and (Aim 3) investigate how CHD4 mutations lead to CM immaturity and cardiac diseases. By defining CHD4's role in postnatal CM maturation and demonstrating its distinct interactome, we expect to understand how CHD4 mutations result in CM immaturity and heart diseases. This research will provide a foundation for developing new therapeutic strategies for heart disease and enhance the clinical application of PSC-CMs in cardiac regenerative medicine.