title: The primary microRNA-208b interacts with Polycomb-group protein, Ezh2, to regulate gene expression in the heart.
abstract: 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.
authors.affiliation: Epigenetics in Human Health and Disease Laboratory, The Alfred Medical Research and Education Precinct, Melbourne, Victoria 3004, Australia, Experimental Cardiology, Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria 3004, Australia, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia and Central Clinical School, Faculty of Medicine, Monash University, Victoria, Australia.
authors.forename: Prabhu
authors.initials: P
authors.lastname: Mathiyalagan
authors.forename: Jun
authors.initials: J
authors.lastname: Okabe
authors.forename: Lisa
authors.initials: L
authors.lastname: Chang
authors.forename: Yidan
authors.initials: Y
authors.lastname: Su
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Du
authors.forename: Assam
authors.initials: A
authors.lastname: El-Osta
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D005786:Gene Expression Regulation; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016372:RNA, Antisense / Q000378:metabolism; D022661:RNA, Untranslated
chemical_list: D002843:Chromatin; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D035683:MicroRNAs; C543978:Mirn208 microRNA, mouse; D016372:RNA, Antisense; D022661:RNA, Untranslated; C012589:trichostatin A; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2; D018995:Myosin Heavy Chains