Mutations in the histone methyltransferase KMT2D are associated with Kabuki Syndrome – a haploinsufficient congenital, multi-organ syndrome that frequently includes severe heart defects. However, the role of KMT2D in the heart has not been analysed in detail. Benoit Bruneau and colleagues now address this (810), generating several conditional Kmt2d mouse mutants and analysing them both phenotypically and using genome-wide approaches. They find that cardiac deletion of Kmt2d causes embryonic lethality with defects in heart morphology and cardiomyocyte proliferation. Global gene expression analysis demonstrates dysregulation of genes associated with cell cycle regulation, ion homeostasis and hypoxia signalling. Functionally, ventricular calcium handling appears impaired. KMT2D is involved in H3K4 mono- and di-methylation; consistent with this, ChIP-Seq data demonstrate that Kmt2d depletion causes loss of H3K4me1 and me2 at specific loci. By correlating these data with the RNA-seq profiles and ChIP-Exo data for KMT2D chromatin binding, the authors are able to identify a small number of high-confidence targets for KMT2D, functions of which are consistent with the phenotypes observed upon Kmt2d deletion. As well as shedding light on the important role of KMT2D in mouse heart development, these data may have implications for the aetiology of the heart defects observed in Kabuki syndrome.
At the heart of histone methylation
At the heart of histone methylation. Development 1 March 2016; 143 (5): e0503. doi:
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