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 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.
a Epigenetics in Human Health and Disease Laboratory; Baker IDI Heart and Diabetes Institute ; Melbourne , Victoria , Australia.
Jenny Y Y
JY
Ooi
Natasha K
NK
Tuano
Haloom
H
Rafehi
Xiao-Ming
XM
Gao
Mark
M
Ziemann
Xiao-Jun
XJ
Du
Assam
A
El-Osta
D000107:Acetylation / Q000187:drug effects*; D000818:Animals; D001011:Aorta / Q000601:surgery; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000601:surgery; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D016328:NF-kappa B; C012589:trichostatin A; D006655:Histone Deacetylases
ANP, Atrial natriuretic peptide; BNP, Brain natriuretic peptide; BW, Body Weight; ChIP, Chromatin Immunoprecipitation; Ct, threshold cycle number; Cxcl10, Chemokine (C-X-C Motif) ligand 10; ENCODE, Encyclopedia of DNA Elements Consortium; FDR, False Discovery Rate; FS, Fractional Shortening; GAIIx, Genome Analyzer IIx; HDAC inhibitor; HDAC, Histone deacetylase; Icam1, Intercellular adhesion molecule 1; Il21r, Interleukin-21 receptor; Il6ra, Interleukin-6 receptor; LV, Left Ventricle; LVDd, Left Ventricular Diastolic Dimension; LVH, Left Ventricle Hypertrophy; MACs, Model-based Analysis of ChIP-seq; NES, normalized enrichment score; NFκB, Nuclear factor of kappa light polypeptide gene enhancer in B-cells; NGS, Next Generation Sequencing; SEM, Standard Error of the Mean; Serca2a, Sarcoplasmic reticulum Ca2+ ATPase; TAC veh, TAC vehicle; TAC, Transverse Aortic Constriction; TF, transcription factor; TL, Tibia Length; TSA, Trichostatin A; TSS, Transcription Start Site; Ticam2, Toll-like receptor adaptor molecule 2; Traf3, TNF receptor-associated factor 3; UTR, Untranslated region; Vcam1, Vascular cell adhesion molecule 1; cDNA, complementary DNA; cardiac hypertrophy; chromatin; epigenetics; histone acetylation; next generation sequencing; α/βMHC, Alpha/Beta myosin heavy chain