GSE154518
Temporal Analyses of Cardiac Chromatin Accessibility, DNA Methylation and Epigenomic Structure Reveal Locus-Specific Regulation [ATAC-seq]
Heart failure can be induced or ameliorated by regulation of chromatin modifying enzymes. Because so many chromatin factors regulate gene expression, we used ATAC-seq to report the status of a given locus at any time—the sum total of all epigenetic modifiers—in a mouse model of pressure overload hypertrophy. Early compensation of pressure overload at 3 days was associated with widespread changes in chromatin accessibility and DNA methylation, the majority of which persisted to the decompensated phase (3 weeks), revealing the temporal nature of epigenomic compensation to pathologic stimuli. A cardiac-specific CTCF depletion model was used to examine how this protein maintains basal cardiac chromatin function and revealed that loss of CTCF causes widespread changes in accessibility and methylation that are distinct from those in pressure overload. Less than half of the gene expression changes occurring at either time point after pressure overload were explained by the actions of DNA methylation alone and accessibility was likewise an imperfect predictor of transcription. Distal enhancers were paired with genes based on chromatin structural data and the regulatory actions of these elements examined in the context of DNA methylation and accessibility: enhancer actions require specific combinations of transcription factors and histone modifications at different stages of disease and to execute a specific transcriptional event (methylation and accessibility alone were insufficient to predict the behavior). In summary, these studies characterize the logic employed at different coding, regulatory, and noncoding regions to regulate chromatin accessibility and transcription, providing a resource of epigenomic data at distinct temporal stages of heart failure. Overall design: Diferences in chromatin accessibility, DNA methylation and gene expression at early (3 days) and late (3 weeks) stage of cardiac disease, and during cardiac-specific CTCF depletion. TAC (transverse aortic constriction) samples represent mice with diseased hearts.