GSE63590
Pharmacological HDAC inhibition attenuates cardiac hypertrophy and histone acetylation of target genes
Cardiac hypertrophy is characterized by an increase in heart size and profound gene expression changes. Pharmacological histone deacetylase (HDAC) inhibitors attenuate pathological cardiac remodeling and hypertrophic gene expression. Published literature has linked enzymes that mediates histone acetylation to pathogenesis, however, the role of histone acetylation to define hypertrophic gene regulatory events are not well understood. We used chromatin immunoprecipitation (ChIP) coupled with massive parallel sequencing (seq) to comprehensively examine genome-wide histone acetylation changes in a pre-clinical model of pathological cardiac hypertrophy by transverse aortic constricted (TAC). We examined the gene targets conferred by the prototypical HDAC inhibitor Trichostatin A (TSA). TSA induces genome-wide histone acetylation and deacetylation in the heart. Alterations to histone acetylation were found on genes involved in cardiac morphology such as cardiac contraction, collagen deposition, inflammation and extracellular matrix. Gene set enrichment analysis identified NF-kappa B (NFKB), as a transcription factor positively correlated with TAC and negatively correlated with TSA by ChIP-seq. Histone acetylation on the promoters of NKFB target genes was increased, consistent with gene activation. In contrast, the promoters of these genes were deacetylated by TSA in hypertrophic animals and reduced expression of NFKB target genes. Our results suggest a potential mechanism for TSA mediated cardioprotection conferred by histone deacetylation of target genes implicating the importance of inflammation. Overall design: ChIP-seq profiles for histone acetylation in left ventricles of mice that develop cardiac hypertrophy and treated with HDAC inhibitors were generated by deep sequencing, using Illumina GAIIx.