Genome-wide fetalization of enhancer architecture in heart disease

Heart disease is associated with re-expression of key transcription factors normally active only during prenatal development of the heart. However, the impact of this reactivation on the regulatory landscape in heart disease is unclear. Here, we use RNA-seq and ChIP-seq targeting a histone modification associated with active transcriptional enhancers to generate genome-wide enhancer maps from left ventricle tissue from up to 26 healthy controls, 18 individuals with idiopathic dilated cardiomyopathy (DCM), and five fetal hearts. Healthy individuals have a highly reproducible epigenomic landscape, consisting of more than 33,000 predicted heart enhancers. In contrast, we observe reproducible disease-associated changes in activity at 6,850 predicted heart enhancers. Combined analysis of adult and fetal samples reveals that the heart disease epigenome and transcriptome both acquire fetal-like characteristics, with 3,400 individual enhancers sharing fetal regulatory properties. We also provide a comprehensive data resource (http://heart.lbl.gov) for the mechanistic exploration of DCM etiology. [Display omitted] •Enhancer and transcriptome maps of healthy, disease-affected, and fetal heart tissue•Highly reproducible epigenomic landscape in healthy individuals•Disease-associated changes in activity at 6,850 predicted heart enhancers•3,400 disease-associated enhancers with fetal regulatory properties Spurrell et al. analyze the transcriptomes and epigenomes of cardiac tissue from healthy individuals and patients with dilated cardiomyopathy, and identify reproducible shifts in the global regulatory landscape. Comparison with fetal heart tissue samples reveals that thousands of predicted enhancer sequences revert to fetal-like chromatin states in heart disease.