Word count: 5331 (excluding references and legends)Short title: Promoter and enhancer shifts in heart failure ABSTRACTThe failed heart is characterized by re-expression of a fetal gene program, which contributes to adaptation and maladaptation in heart failure. To define genomewide enhancer and promoter use in heart failure, Cap Analysis of Gene Expression (CAGE-seq) was applied to healthy and failed human left ventricles to define short RNAs associated with both promoters and enhancers. Integration of CAGE-seq data with RNA sequencing identified a combined ~17,000 promoters and ~1,500 enhancers active in healthy and failed human left ventricles. Comparing promoter usage between healthy and failed hearts highlighted promoter shifts which altered amino-terminal protein sequences. Comparing enhancer usage between healthy and failed hearts revealed a majority of differentially utilized heart failure enhancers were intronic and primarily localized within the first intron, identifying this position as a common feature associated with tissue-specific gene expression changes in the heart. This dataset defines the dynamic genomic regulatory landscape underlying heart failure and serves as an important resource for understanding genetic contributions to cardiac dysfunction. Wang from the Northwestern University sequencing core and Yujiro Takegami from DNAFORM for their excellent technical support. AG conducted the analysis and drafted the mansuscript. LDC secured patient consent and genotype information. PP assisted with genotyping. JAW provided access to control samples. DYB and MJP provided helpful advice and commentary and assisted with interpretation. MAN and EMM assisted with analysis, writing and editing the manuscript.
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