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Genome Res. 2014 Aug;24(8):1271-84. doi: 10.1101/gr.168781.113. Epub 2014 Apr 14.

Vascular histone deacetylation by pharmacological HDAC inhibition.

Author information

1
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia; Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia;
2
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia;
3
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia; Faculty of Medicine, Monash University, Victoria 3800, Australia.
4
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia; Faculty of Medicine, Monash University, Victoria 3800, Australia assam.el-osta@bakeridi.edu.au.
5
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.

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.

PMID:
24732587
PMCID:
PMC4120081
DOI:
10.1101/gr.168781.113
[Indexed for MEDLINE]
Free PMC Article

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