HDAC inhibition attenuates cardiac hypertrophy by acetylation and deacetylation of target genes

Pharmacological histone deacetylase (HDAC) inhibitors attenuate pathological cardiac remodeling and hypertrophic gene expression; yet, the direct histone targets remain poorly characterized. Since the inhibition of HDAC activity is associated with suppressing hypertrophy, we hypothesized histone ace...

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Published in:	Epigenetics Vol. 10; no. 5; pp. 418 - 430
Main Authors:	Ooi, Jenny Y Y, Tuano, Natasha K, Rafehi, Haloom, Gao, Xiao-Ming, Ziemann, Mark, Du, Xiao-Jun, El-Osta, Assam
Format:	Journal Article
Language:	English
Published:	United States Taylor & Francis 04.05.2015
Subjects:	Acetylation - drug effects Animals Aorta - surgery cardiac hypertrophy Cardiomegaly - genetics Cardiomegaly - metabolism Cardiomegaly - surgery chromatin epigenetics Gene Expression Regulation - drug effects HDAC inhibitor histone acetylation Histone Deacetylase Inhibitors - pharmacology Histone Deacetylases - metabolism Histones - metabolism Hydroxamic Acids - pharmacology Male Mice, Inbred C57BL Myocardium - metabolism next generation sequencing NF-kappa B - metabolism Research Paper NFκB, Nuclear factor of kappa light polypeptide gene enhancer in B-cells Icam1, Intercellular adhesion molecule 1 LVH, Left Ventricle Hypertrophy cDNA, complementary DNA TF, transcription factor Il21r, Interleukin-21 receptor Serca2a, Sarcoplasmic reticulum Ca2+ ATPase TSS, Transcription Start Site epigenetics SEM, Standard Error of the Mean BW, Body Weight Il6ra, Interleukin-6 receptor Cxcl10, Chemokine (C-X-C Motif) ligand 10 FDR, False Discovery Rate NES, normalized enrichment score TAC, Transverse Aortic Constriction MACs, Model-based Analysis of ChIP-seq GAIIx, Genome Analyzer IIx Traf3, TNF receptor-associated factor 3 BNP, Brain natriuretic peptide ChIP, Chromatin Immunoprecipitation next generation sequencing NGS, Next Generation Sequencing chromatin HDAC, Histone deacetylase Vcam1, Vascular cell adhesion molecule 1 Ct, threshold cycle number TAC veh, TAC vehicle ANP, Atrial natriuretic peptide TSA, Trichostatin A HDAC inhibitor α/βMHC, Alpha/Beta myosin heavy chain ENCODE, Encyclopedia of DNA Elements Consortium FS, Fractional Shortening LVDd, Left Ventricular Diastolic Dimension UTR, Untranslated region cardiac hypertrophy Ticam2, Toll-like receptor adaptor molecule 2 histone acetylation LV, Left Ventricle TL, Tibia Length
ISSN:	1559-2294, 1559-2308
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Summary:	Pharmacological histone deacetylase (HDAC) inhibitors attenuate pathological cardiac remodeling and hypertrophic gene expression; yet, the direct histone targets remain poorly characterized. Since the inhibition of HDAC activity is associated with suppressing hypertrophy, we hypothesized histone acetylation would target genes implicated in cardiac remodeling. Trichostatin A (TSA) regulates cardiac gene expression and attenuates transverse aortic constriction (TAC) induced hypertrophy. We used chromatin immunoprecipitation (ChIP) coupled with massive parallel sequencing (ChIP-seq) to map, for the first time, genome-wide histone acetylation changes in a preclinical model of pathological cardiac hypertrophy and attenuation of pathogenesis with TSA. Pressure overload-induced cardiac hypertrophy was associated with histone acetylation of genes implicated in cardiac contraction, collagen deposition, inflammation, and extracellular matrix identified by ChIP-seq. Gene set enrichment analysis identified NF-kappa B (NF-κB) transcription factor activation with load induced hypertrophy. Increased histone acetylation was observed on the promoters of NFκB target genes (Icam1, Vcam1, Il21r, Il6ra, Ticam2, Cxcl10) consistent with gene activation in the hypertrophied heart. Surprisingly, TSA attenuated pressure overload-induced cardiac hypertrophy and the suppression of NFκB target genes by broad histone deacetylation. Our results suggest a mechanism for cardioprotection subject to histone deacetylation as a previously unknown target, implicating the importance of inflammation by pharmacological HDAC inhibition. The results of this study provides a framework for HDAC inhibitor function in the heart and argues the long held views of acetylation is subject to more flexibility than previously thought.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1559-2294 1559-2308
DOI:	10.1080/15592294.2015.1024406