An atlas of transcribed human cardiac promoters and enhancers reveals an important role of regulatory elements in heart failure

In this work we present atlas of human cardiac regulatory elements defined by CAGE (cap analysis of gene expression) technique. The dataset includes right and left atria and ventricles form both healthy and failing samples. The deep sequencing of CAGE libraries on Illumina HiSeq2500, mapping, and signal clustering resulted in identification of 65,458 CAGE peaks, from which 55,204 were robust decomposition peak identifiers (DPIs) and 10,254 bidirectional enhancers. We created comprehensive classification of the peaks by applying machine learning along with annotation from available databases containing cardiac data. Identified CAGE peaks were arranged into non-overlapping 400 bp consensus clusters. Our classification method determined 17,668 promoters and 14,920 enhancers active in the human heart. Differential expression analysis revealed regulatory elements activated or inactivated in healthy or failing states. About 10% of heart related GWAS SNPs were found to be located around heart CAGE clusters. The library of cardiac promoters and enhancers is available in Zenbu reports for browsing and visualization. Superior and inferior sinoatrial node samples are labeled as sSAN and iSAN, respectively. Overall design: In total 109 samples from 31 human hearts were freshly collected and were either flash frozen in liquid nitrogen or stored in RNAlater. Total RNA was extracted with RNeasy Fibrous Tissue Mini Kit and CAGE libraries prepared with ssCAGE or nAnT-iCAGE. Libraries were sequenced on Illumina HiSeq2500.