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BS26 Role of KMT2C, a histone methyltransferase in the development of compacted myocardium
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  1. Sabu Abraham
  1. University of Manchester, Core Technology Facility, 46 Grafton Street, Manchester, GTM M13 9NT UK

Abstract

Epigenetic gene regulation has been increasingly established as a pivotal molecular mechanism driving heart development and its aberrant regulation has been implicated in congenital heart diseases. KMT2C is a histone methyltransferase enzyme that mediates the Histone 3 lysine 4 (H3K4) methylation that denotes active promoters and enhancers. Our previous work identified a number of de novo variants in KMT2C gene in nonsyndromic Tetralogy of Fallot patients. Global deletion of delta SET domain region of Kmt2c gene that harbour methyltransferase enzymatic activity resulted in neonatal lethality in mice. Histological analysis of knockout mice embryonic heart revealed ventricular septal defect (with and without an overriding aorta) with a low penetrance but also displayed a consistent phenotype resembling ventricular non-compaction. Embryonic hearts from the knockout mice at the e16.5 stage of development displayed a significantly thinner (p<0.05) compact myocardium of the left ventricle compared to the wild-type littermates. In order to get insights into the molecular mechanism for this phenotype, we carried out RNA sequencing experiments in ventricles of e16.5 embryonic hearts from mice with a homozygous deletion and wild type littermates. A significant decrease in gene expression is observed in many of the extracellular matrix (ECM) genes, especially elastin (p<1.0E-6), various subtypes of collagens, fibronectin, and integrins. We also found an altered expression of genes important for ECM homeostasis, e.g. MMPs, and ventricular trabeculation/compaction, e.g. Notch1. ECM is known to play important role in heart development, including trabeculation and formation of compacted myocardium. Our data suggest an important role played by Kmt2c in regulating ECM homeostasis and the formation of compacted myocardium.

  • Epigenetic regulation
  • Congenital heart disease
  • Extra cellular matrix

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