Abstract
While global changes in gene expression are a hallmark of heart disease, much less is known regarding the epigenetic factors driving these changes. Local chromatin packing and gene accessibility, which governs transcriptional status, has been correlated with specific post‐translational modifications (PTMs) on the histone tails of nucleosomes occupying these regions. However, the specific alterations in histone PTMs driving the conserved gene expression changes observed in heart disease and how these ultimately affect cardiac physiology are largely unknown. To identify changes in histone PTMs during disease progression, we performed label‐free quantitation of acid‐extracted proteins from mouse heart (under basal, hypertrophic, and failing conditions) and from isolated ventricular myocytes exposed to hypertrophic agonists, a cell model of cardiac hypertrophy. Protein samples were propionylated, enzymatically digested and analyzed on an Orbitrap Velos mass spectrometer and differential expression analysis was performed using MaxQuant and Perseus software. Collectively we identified 55 and 30 PTMs spanning the five histone families, from cardiac tissue and isolated myocytes, respectively, 16 of which were differentially regulated in the setting of disease. Additionally our analysis of large peptides containing multiple PTMs enabled us to determine how these modifications are regulated with respect to one another providing insights into the broader histone code. This study presents the first global characterization of histone post‐translational modifications in the heart and highlights basic mechanisms of genomic reprogramming operative in disease.
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