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An essential role for H3K4 methyltransferase KMT2D in heart development

  • Author(s): Ang, Siang Yun
  • Advisor(s): Bruneau, Benoit G
  • et al.
Abstract

Heart development is a complex process that requires tightly regulated cardiac gene expression. One important control is through dynamic changes in chromatin structure. Methylation of histone H3 lysine 4 (H3K4) has been linked to transcriptional activation at associated gene loci. Mutations in KMT2D (MLL2/ALR), which encodes for an H3K4 methyltransferase, lead to Kabuki syndrome, and patients present with congenital heart defects. We hypothesize that Kmt2d, and thus H3K4 methylation, are required for normal cardiac gene expression and heart development.

Although KMT2D haploinsufficiency causes Kabuki syndrome in humans, mice lacking one allele of Kmt2d develop through adulthood with normal cardiac morphology and function. To define the requirement for Kmt2d in cardiogenesis, we deleted Kmt2d in mesodermal precursors and anterior heart field precursors. Mesodermal deletion of Kmt2d led to embryonic lethality at E10.5 with severely hypoplastic hearts, whereas deletion in the anterior heart field led to embryonic lethality at E13.5 with outflow tract abnormalities and ventricular septal defects (VSDs). To determine the cell type responsible for these cardiac defects, we deleted Kmt2d in the myocardium, which led to embryonic lethality at E14.5 with VSDs and thin compact myocardium.

Specific gene expression programs were dysregulated in each deletion mutant, indicating that Kmt2d regulates distinct gene subsets in different cardiac cell populations. Interestingly, gene expression analysis revealed common overrepresented GO categories between the three cardiac deletion mutants, including downregulation of ion transport genes and upregulation of hypoxia response genes.

We further determined that myocardial deletion of Kmt2d leads to a decrease in H3K4me2 levels at promoters and at H3K27Ac-enriched enhancers. H3K4me1 levels were also decreased at enhancers, but H3K4me3 levels remained unchanged. Comparison with gene expression data revealed that multiple ion transport genes had decreased H3K4me2 and decreased expression in the absence of Kmt2d, suggesting a novel role for KMT2D in the regulation of ion transport genes via H3K4 di-methylation.

Overall, our work demonstrates a critical requirement for Kmt2d in cardiac precursors and myocardium during embryonic development. Our results also indicate that KMT2D, through its role as a H3K4 di-methyltransferase in the myocardium, is essential for regulating cardiac gene expression during heart development.

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