Altered Enhancer and Promoter Usage Leads to Differential Gene Expression in the Normal and Failed Human Heart.

ABSTRACT

BACKGROUND: The failing heart is characterized by changes in gene expression. However, the regulatory regions of the genome that drive these gene expression changes have not been well defined in human hearts. METHODS: To define genome-wide enhancer and promoter use in heart failure, cap analysis of gene expression sequencing was applied to 3 healthy and 4 failed human hearts to identify promoter and enhancer regions used in left ventricles. Healthy hearts were derived from donors unused for transplantation and failed hearts were obtained as discarded tissue after transplantation. RESULTS: Cap analysis of gene expression sequencing identified a combined potential for ≈23 000 promoters and ≈5000 enhancers active in human left ventricles. Of these, 17 000 promoters and 1800 enhancers had additional support for their regulatory function. Comparing promoter usage between healthy and failed hearts highlighted promoter shifts which altered aminoterminal protein sequences. Enhancer usage between healthy and failed hearts identified a majority of differentially used heart failure enhancers were intronic and primarily localized within the first intron, revealing this position as a common feature associated with tissue-specific gene expression changes in the heart. CONCLUSIONS: This data set defines the dynamic genomic regulatory landscape underlying heart failure and serves as an important resource for understanding genetic contributions to cardiac dysfunction. Additionally, regulatory changes contributing to heart failure are attractive therapeutic targets for controlling ventricular remodeling and clinical progression.