title: Vascular histone deacetylation by pharmacological HDAC inhibition.
abstract: HDAC inhibitors can regulate gene expression by post-translational modification of histone as well as nonhistone proteins. Often studied at single loci, increased histone acetylation is the paradigmatic mechanism of action. However, little is known of the extent of genome-wide changes in cells stimulated by the hydroxamic acids, TSA and SAHA. In this article, we map vascular chromatin modifications including histone H3 acetylation of lysine 9 and 14 (H3K9/14ac) using chromatin immunoprecipitation (ChIP) coupled with massive parallel sequencing (ChIP-seq). Since acetylation-mediated gene expression is often associated with modification of other lysine residues, we also examined H3K4me3 and H3K9me3 as well as changes in CpG methylation (CpG-seq). RNA sequencing indicates the differential expression of ∼30% of genes, with almost equal numbers being up- and down-regulated. We observed broad deacetylation and gene expression changes conferred by TSA and SAHA mediated by the loss of EP300/CREBBP binding at multiple gene promoters. This study provides an important framework for HDAC inhibitor function in vascular biology and a comprehensive description of genome-wide deacetylation by pharmacological HDAC inhibition.
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia; Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: Haloom
authors.initials: H
authors.lastname: Rafehi
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia;
authors.forename: Aneta
authors.initials: A
authors.lastname: Balcerczyk
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Lunke
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia;
authors.forename: Antony
authors.initials: A
authors.lastname: Kaspi
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia;
authors.forename: Mark
authors.initials: M
authors.lastname: Ziemann
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia;
authors.forename: Harikrishnan
authors.initials: H
authors.lastname: Kn
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia; Faculty of Medicine, Monash University, Victoria 3800, Australia.
authors.forename: Jun
authors.initials: J
authors.lastname: Okabe
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia;
authors.forename: Ishant
authors.initials: I
authors.lastname: Khurana
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia;
authors.forename: Jenny
authors.initials: J
authors.lastname: Ooi
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia;
authors.forename: Abdul Waheed
authors.initials: AW
authors.lastname: Khan
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia; Faculty of Medicine, Monash University, Victoria 3800, Australia assam.el-osta@bakeridi.edu.au.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Du
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia;
authors.forename: Lisa
authors.initials: L
authors.lastname: Chang
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia;
authors.forename: Izhak
authors.initials: I
authors.lastname: Haviv
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia;
authors.forename: Samuel T
authors.initials: ST
authors.lastname: Keating
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia;
authors.forename: Tom C
authors.initials: TC
authors.lastname: Karagiannis
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia; Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia; Faculty of Medicine, Monash University, Victoria 3800, Australia assam.el-osta@bakeridi.edu.au.
authors.forename: Assam
authors.initials: A
authors.lastname: El-Osta
mesh_terms: D000107:Acetylation; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001011:Aorta / Q000166:cytology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects; D015894:Genome, Human; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D014157:Transcription Factors / Q000378:metabolism; D059467:Transcriptome; D000077337:Vorinostat
chemical_list: D000893:Anti-Inflammatory Agents; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D014157:Transcription Factors; C012589:trichostatin A; D000077337:Vorinostat
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