title: Chromatin modifications remodel cardiac gene expression.
abstract: Signalling and transcriptional control involve precise programmes of gene activation and suppression necessary for cardiovascular physiology. Deep sequencing of DNA-bound transcription factors reveals a remarkable complexity of co-activators or co-repressors that serve to alter chromatin modification and regulate gene expression. The regulated complexes characterized by genome-wide mapping implicate the recruitment and exchange of proteins with specific enzymatic activities that include roles for histone acetylation and methylation in key developmental programmes of the heart. As for transcriptional changes in response to pathological stress, co-regulatory complexes are also differentially utilized to regulate genes in cardiac disease. Members of the histone deacetylase (HDAC) family catalyse the removal of acetyl groups from proteins whose pharmacological inhibition has profound effects preventing heart failure. HDACs interact with a complex co-regulatory network of transcription factors, chromatin-remodelling complexes, and specific histone modifiers to regulate gene expression in the heart. For example, the histone methyltransferase (HMT), enhancer of zeste homolog 2 (Ezh2), is regulated by HDAC inhibition and associated with pathological cardiac hypertrophy. The challenge now is to target the activity of enzymes involved in protein modification to prevent or reverse the expression of genes implicated with cardiac hypertrophy. In this review, we discuss the role of HDACs and HMTs with a focus on chromatin modification and gene function as well as the clinical treatment of heart failure.
authors.affiliation: Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria 3004, Australia.
authors.forename: Prabhu
authors.initials: P
authors.lastname: Mathiyalagan
authors.affiliation: Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria 3004, Australia.
authors.forename: Samuel T
authors.initials: ST
authors.lastname: Keating
authors.affiliation: Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria 3004, Australia Central Clinical School, Faculty of Medicine, Monash University, Victoria, Australia.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Du
authors.affiliation: Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria 3004, Australia Central Clinical School, Faculty of Medicine, Monash University, Victoria, Australia Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia assam.el-osta@bakeridi.edu.au.
authors.forename: Assam
authors.initials: A
authors.lastname: El-Osta
mesh_terms: D000107:Acetylation; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D000071221:Enhancer of Zeste Homolog 2 Protein; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D008955:Models, Cardiovascular; D009206:Myocardium / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2 / Q000172:deficiency / Q000235:genetics; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction
chemical_list: D002843:Chromatin; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D000076983:Histone Methyltransferases; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; D006655:Histone Deacetylases
keywords: Cardiac hypertrophy; Chromatin remodelling; Gene regulation; Histone acetylation; Histone methylation