The role of KMT2D and KDM6A in cardiac development: A cross-species analysis in humans, mice, and zebrafish
AbstractCongenital Heart Defects (CHDs) are the most common form of birth defects, observed in 4-10/1000 live births. CHDs result in a wide range of structural and functional abnormalities of the heart which significantly affect quality of life and mortality. CHDs are often seen in patients with mutations in epigenetic regulators of gene expression, like the genes implicated in Kabuki syndrome – KMT2D and KDM6A, which play important roles in normal heart development and function. Here, we examined the role of two epigenetic histone modifying enzymes, KMT2D and KDM6A, in the expression of genes associated with early heart and neural crest cell (NCC) development. Using CRISPR/Cas9 mediated mutagenesis of kmt2d, kdm6a and kdm6al in zebrafish, we show cardiac and NCC gene expression is reduced, which correspond to affected cardiac morphology and reduced heart rates. To translate our results to a human pathophysiological context and compare transcriptomic targets of KMT2D and KDM6A across species, we performed RNA sequencing (seq) of lymphoblastoid cells from Kabuki Syndrome patients carrying mutations in KMT2D and KDM6A. We compared the human RNA-seq datasets with RNA-seq datasets obtained from mouse and zebrafish. Our comparative interspecies analysis revealed common targets of KMT2D and KDM6A, which are shared between species, and these target genes are reduced in expression in the zebrafish mutants. Taken together, our results show that KMT2D and KDM6A regulate common and unique genes across humans, mice, and zebrafish for early cardiac and overall development that can contribute to the understanding of epigenetic dysregulation in CHDs.