Vascular histone deacetylation by pharmacological HDAC inhibition
- Haloom Rafehi1,2,
- Aneta Balcerczyk1,4,
- Sebastian Lunke1,5,
- Antony Kaspi1,
- Mark Ziemann1,
- Harikrishnan KN1,
- Jun Okabe1,3,
- Ishant Khurana1,
- Jenny Ooi1,
- Abdul Waheed Khan1,
- Xiao-Jun Du1,3,
- Lisa Chang1,
- Izhak Haviv1,4,
- Samuel T. Keating1,
- Tom C. Karagiannis1 and
- Assam El-Osta1,2,3
- 1Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia;
- 2Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia;
- 3Faculty of Medicine, Monash University, Victoria 3800, Australia
- Corresponding author: assam.el-osta{at}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.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.168781.113.
- Received October 26, 2013.
- Accepted April 9, 2014.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.