Genome-Wide Fetalization of Enhancer Architecture in Heart Disease

Spurrell, C. H.; Barozzi, I.; Mannion, B. J.; Blow, M. J.; Fukuda-Yuzawa, Y.; Afzal, S. Y.; Akiyama, J. A.; Afzal, V.; Tran, S.; Plajzer-Frick, I.; Novak, C. S.; Kato, M.; Lee, E.; Garvin, T. H.; Pham, Q. T.; Harrington, A. N.; Lisgo, S.; Bristow, J.; Cappola, T. P.; Morley, M. P.; Margulies, K. B.; Pennacchio, L. A.; Dickel, D. E.; Visel, A.

doi:10.1101/591362

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bioRxiv · 10.1101/591362

Genome-Wide Fetalization of Enhancer Architecture in Heart Disease

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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.

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Spurrell, C. H., Barozzi, I., Mannion, B. J., Blow, M. J., Fukuda-Yuzawa, Y., Afzal, S. Y., Akiyama, J. A., Afzal, V., Tran, S., Plajzer-Frick, I., Novak, C. S., Kato, M., Lee, E., Garvin, T. H., Pham, Q. T., Harrington, A. N., Lisgo, S., Bristow, J., Cappola, T. P., Morley, M. P., Margulies, K. B., Pennacchio, L. A., Dickel, D. E., Visel, A.. 2019-04-01. Genome-Wide Fetalization of Enhancer Architecture in Heart Disease. https://doi.org/10.1101/591362

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