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Vascular histone deacetylation by pharmacological HDAC inhibition

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journal contribution
posted on 2014-08-01, 00:00 authored by Haloom Rafehi, Aneta Balcerczyk, Sebastian Lunke, Antony Kaspi, Mark ZiemannMark Ziemann, Harikrishnan Kn, Jun Okabe, Ishant Khurana, Jenny Ooi, Abdul Waheed Khan, Xiao-Jun Du, Lisa Chang, Izhak Haviv, Samuel T Keating, Tom C Karagiannis, Assam El-Osta
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.

History

Journal

Genome research

Volume

24

Pagination

1271-1284

Location

Cold Spring Harbor, N.Y.

eISSN

1549-5469

Language

eng

Publication classification

C1.1 Refereed article in a scholarly journal

Copyright notice

2014, Rafehi et al.

Issue

8

Publisher

Cold Spring Harbor Laboratory Press