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
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ISSN:1559-2294, 1559-2308
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Abstract 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.
AbstractList 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.
Author Ooi, Jenny Y Y
Rafehi, Haloom
El-Osta, Assam
Gao, Xiao-Ming
Tuano, Natasha K
Du, Xiao-Jun
Ziemann, Mark
Author_xml – sequence: 1
  givenname: Jenny Y Y
  surname: Ooi
  fullname: Ooi, Jenny Y Y
  organization: Epigenetics in Human Health and Disease Laboratory; Baker IDI Heart and Diabetes Institute
– sequence: 2
  givenname: Natasha K
  surname: Tuano
  fullname: Tuano, Natasha K
  organization: Epigenetics in Human Health and Disease Laboratory; Baker IDI Heart and Diabetes Institute
– sequence: 3
  givenname: Haloom
  surname: Rafehi
  fullname: Rafehi, Haloom
  organization: Department of Pathology; University of Melbourne
– sequence: 4
  givenname: Xiao-Ming
  surname: Gao
  fullname: Gao, Xiao-Ming
  organization: Experimental Cardiology Laboratory; Baker IDI Heart and Diabetes Institute
– sequence: 5
  givenname: Mark
  surname: Ziemann
  fullname: Ziemann, Mark
  organization: Epigenetics in Human Health and Disease Laboratory; Baker IDI Heart and Diabetes Institute
– sequence: 6
  givenname: Xiao-Jun
  surname: Du
  fullname: Du, Xiao-Jun
  organization: Faculty of Medicine; Monash University
– sequence: 7
  givenname: Assam
  surname: El-Osta
  fullname: El-Osta, Assam
  email: assam.el-osta@bakeridi.edu.au
  organization: Department of Pathology; University of Melbourne
BackLink https://www.ncbi.nlm.nih.gov/pubmed/25941940$$D View this record in MEDLINE/PubMed
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Issue 5
Keywords 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
Language English
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Snippet Pharmacological histone deacetylase (HDAC) inhibitors attenuate pathological cardiac remodeling and hypertrophic gene expression; yet, the direct histone...
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StartPage 418
SubjectTerms 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
Title HDAC inhibition attenuates cardiac hypertrophy by acetylation and deacetylation of target genes
URI https://www.tandfonline.com/doi/abs/10.1080/15592294.2015.1024406
https://www.ncbi.nlm.nih.gov/pubmed/25941940
https://www.proquest.com/docview/1681267059
https://pubmed.ncbi.nlm.nih.gov/PMC4622459
Volume 10
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