Role of histone modifications and chromatin interacting non-coding RNAs in regulating cardiac gene transcription
thesisposted on 23.02.2017 by Mathiyalagan, Prabhu
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Pathological hypertrophy induced ventricular remodeling is intimately associated with chromatin regulatory events. Epigenetic modifying enzymes such as DNA methyltransferases (DNMT) and histone deacetylases (HDAC), in complex with chromatin remodeling proteins such as Brg1 and PARP, mediate stress induced pathological signaling within the myocardium. The HDAC inhibitor, trichostatin A (TSA) effectively attenuates pathological hypertrophy. The cardioprotection of TSA is characteristic of attenuated fetal gene activation following pathological stress. Specifically, hypertrophy induced beta-MHC expression is prevented and associated with improved left ventricular functioning after TSA administration. Cardiac Myosin heavy chain (MHC) non-coding RNAs (ncRNAs) such as microRNA-208a and -208b as well as the long antisense beta RNA transcript are thought to regulate cardiac MHC gene switch. The study hypothesized and tested that MHC ncRNAs induce cardioprotection conferred by TSA through chromatin targeting events such as histone modifications within the coding regions of alphaand beta-MHC genes.