Abstract
KMT2D, which encodes a histone H3K4 methyltransferase, has been implicated in human congenital heart disease in the context of Kabuki syndrome. However, its role in heart development is not understood. Here, we demonstrate a requirement for KMT2D in cardiac precursors and cardiomyocytes during cardiogenesis in mice. Gene expression analysis revealed downregulation of ion transport and cell cycle genes, leading to altered calcium handling and cell cycle defects. We further determined that myocardial Kmt2d deletion led to decreased H3K4me1 and H3K4me2 at enhancers and promoters. Finally, we identified KMT2D-bound regions in cardiomyocytes, of which a subset was associated with decreased gene expression and decreased H3K4me2 in mutant hearts. This subset included genes related to ion transport, hypoxia-reoxygenation and cell cycle regulation, suggesting that KMT2D is important for these processes. Our findings indicate that KMT2D is essential for regulating cardiac gene expression during heart development primarily via H3K4 di-methylation.
Highlights
During heart development genes are tightly regulated to ensure expression in specific cardiac tissues at the appropriate time
A single copy of Kmt2d is sufficient for normal heart development and leads to mild functional defects Heart development relies on appropriate gene regulation in multiple cell types
We identified an essential role for KMT2D as a regulator of heart development
Summary
During heart development genes are tightly regulated to ensure expression in specific cardiac tissues at the appropriate time. It has emerged that dynamic changes in chromatin structure are crucial in controlling cardiac gene expression, implicating several chromatin remodelers and histone-modifying enzymes in the regulation of heart development, the precise role of many chromatin modifiers remains unknown (Chang and Bruneau, 2012). Each histone mark is associated with specific regulatory elements and functions, indicating a complex control of active gene transcription
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