학술논문
Genome-Wide Fetalization of Enhancer Architecture in Heart Disease
Document Type
article
Author
Spurrell, Cailyn; Barozzi, Iros; Mannion, Brandon; Blow, Matthew; Fukuda-Yuzawa, Yoko; Afzal, Sarah; Akiyama, Jennifer; Afzal, Veena; Tran, Stella; Plajzer-Frick, Ingrid; Novak, Catherine; Kato, Momoe; Lee, Elizabeth; Garvin, Tyler; Pham, Quan; Harrington, Anne; Lisgo, Steven; Bristow, James; Cappola, Thomas; Morley, Michael; Margulies, Kenneth; Pennacchio, Len; Dickel, Diane; Visel, Axel
Source
Subject
Language
Abstract
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 genome-wide regulatory landscape in heart disease has remained obscure. Here we show that pervasive epigenomic changes occur in heart disease, with thousands of regulatory sequences reacquiring fetal-like chromatin signatures. We used 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 18 healthy controls and 18 individuals with idiopathic dilated cardiomyopathy (DCM). Healthy individuals had a highly reproducible epigenomic landscape, consisting of more than 31,000 predicted heart enhancers. In contrast, we observed reproducible disease-associated gains or losses of activity at more than 7,500 predicted heart enhancers. Next, we profiled human fetal heart tissue by ChIP-seq and RNA-seq. Comparison with adult tissues revealed that the heart disease epigenome and transcrip-tome both shift toward a fetal-like state, with 3,400 individual enhancers sharing fetal regulatory properties. Our results demonstrate widespread epigenomic changes in DCM, and we provide a comprehensive data resource ( http://heart.lbl.gov ) for the mechanistic exploration of heart disease etiology.