18 research outputs found

    Role of histone modifications and chromatin interacting non-coding RNAs in regulating cardiac gene transcription

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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

    Role of histone modifications and chromatin interacting non-coding RNAs in regulating cardiac gene transcription

    No full text
    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

    Chromatin modifications remodel cardiac gene expression

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    The primary microRNA-208b interacts with Polycomb-group protein, Ezh2, to regulate gene expression in the heart

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    The Polycomb-group protein, Ezh2, is required for epigenetic gene silencing in the adult heart by unknown mechanism. We investigated the role of Ezh2 and non-coding RNAs in a mouse model of pressure overload using transverse aortic constriction (TAC) attenuated by the prototypical histone deacetylase inhibitor, trichostatin A (TSA). Chromatin immunoprecipitation of TAC and TAC+TSA hearts suggests interaction of Ezh2 and primary microRNA-208b (pri-miR-208b) in the regulation of hypertrophic gene expression. RNAi silencing of pri-miR-208b and Ezh2 validate pri-miR-208b-mediated transcriptional silencing of genes implicated in cardiac hypertrophy including the suppression of the bi-directional promoter (bdP) of the cardiac myosin heavy chain genes. In TAC mouse heart, TSA attenuated Ezh2 binding to bdP and restored antisense β-MHC and α-MHC gene expression. RNA-chromatin immunoprecipitation experiments in TAC hearts also show increased pri-miR-208b dependent-chromatin binding. These results are the first description by which primary miR interactions serve to integrate chromatin modifications and the transcriptional response to distinct signaling cues in the heart. These studies provide a framework for MHC expression and regulation of genes implicated in pathological remodeling of ventricular hypertrophy

    The primary microRNA-208b interacts with Polycomb-group protein, Ezh2, to regulate gene expression in the heart

    Get PDF
    The Polycomb-group protein, Ezh2, is required for epigenetic gene silencing in the adult heart by unknown mechanism. We investigated the role of Ezh2 and non-coding RNAs in a mouse model of pressure overload using transverse aortic constriction (TAC) attenuated by the prototypical histone deacetylase inhibitor, trichostatin A (TSA). Chromatin immunoprecipitation of TAC and TAC+TSA hearts suggests interaction of Ezh2 and primary microRNA-208b (pri-miR-208b) in the regulation of hypertrophic gene expression. RNAi silencing of pri-miR-208b and Ezh2 validate pri-miR-208b-mediated transcriptional silencing of genes implicated in cardiac hypertrophy including the suppression of the bi-directional promoter (bdP) of the cardiac myosin heavy chain genes. In TAC mouse heart, TSA attenuated Ezh2 binding to bdP and restored antisense β-MHC and α-MHC gene expression. RNA-chromatin immunoprecipitation experiments in TAC hearts also show increased pri-miR-208b dependent-chromatin binding. These results are the first description by which primary miR interactions serve to integrate chromatin modifications and the transcriptional response to distinct signaling cues in the heart. These studies provide a framework for MHC expression and regulation of genes implicated in pathological remodeling of ventricular hypertrophy

    Tissue-specific and tissue-agnostic effects of genome sequence variation modulating blood pressure

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    Summary: Genome-wide association studies (GWASs) have identified numerous variants associated with polygenic traits and diseases. However, with few exceptions, a mechanistic understanding of which variants affect which genes in which tissues to modulate trait variation is lacking. Here, we present genomic analyses to explain trait heritability of blood pressure (BP) through the genetics of transcriptional regulation using GWASs, multiomics data from different tissues, and machine learning approaches. Approximately 500,000 predicted regulatory variants across four tissues explain 33.4% of variant heritability: 2.5%, 5.3%, 7.7%, and 11.8% for kidney-, adrenal-, heart-, and artery-specific variants, respectively. Variation in the enhancers involved shows greater tissue specificity than in the genes they regulate, suggesting that gene regulatory networks perturbed by enhancer variants in a tissue relevant to a phenotype are the major source of interindividual variation in BP. Thus, our study provides an approach to scan human tissue and cell types for their physiological contribution to any trait
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