Cardiac genes show contextual SWI/SNF interactions with distinguishable gene activities

Chang, Lisa; Kiriazis, Helen; Gao, Xuemei; Du, Xiao Jun; El‐Osta, Assam

doi:10.4161/epi.6.6.16007

Cited by 26 publications

(22 citation statements)

References 51 publications

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“…remodeling, 46,47 and gene regulation under the control of noncoding RNAs. 48 Recent studies from our laboratory have also indicated that the cooperation between non-coding RNAs integrating chromatin modifications and epigenetic changes regulate hypertrophic gene activity.…”

Section: Discussionmentioning

confidence: 99%

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

Ooi¹,

Tuano

Rafehi³

et al. 2015

Epigenetics

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113

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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-kB) transcription factor activation with load induced hypertrophy. Increased histone acetylation was observed on the promoters of NFkB 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 NFkB 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.

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Section: Discussionmentioning

confidence: 99%

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

Ooi¹,

Tuano

Rafehi³

et al. 2015

Epigenetics

Self Cite

113

View full text Add to dashboard Cite

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“…In vivo mouse model C57BL/6 male mice (10-12 wk old) were injected subcutaneously twice daily at 0.6 mg/kg/day of TSA for 4 wk, as previously described (Chang et al 2011). To study cardiac function, noninvasive echocardiography was used to measure left ventricular (LV) dimensions end-diastole and end-systole as well as LV fractional shortening (FS).…”

Section: Cell Viabilitymentioning

confidence: 99%

“…For gene expression, RNA isolation and cDNA synthesis were performed as previously described. LVs were pooled for one ChIP experiment with H3K9/K14 antibody (06-599, Upstate) and performed as previously described (Chang et al 2011). …”

Section: Cell Viabilitymentioning

confidence: 99%

Vascular histone deacetylation by pharmacological HDAC inhibition

et al. 2014

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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.

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“…44,45 Evidence now indicates the reversibility of cardiac events and parameters associated with hypertrophy by histone deacetylase inhibition, suggesting dynamic assembly of determinants on the chromatinized template is associated with restoring gene expression patterns. 46 In the left ventricle, the experimental evidence implies the distinguishable and opposing roles of Brm and Brg1 in the hypertrophied heart. This was exemplified with the specific expression of ANP (Nppa), BNP (Nppb) and β-MHC (Myh7), which were inversely correlated with a-MHC (Myh6) and Serca2a (Atp2a2) genes.…”

Section: Distinguishing the Genome With Chromatin Modificationsmentioning

confidence: 99%