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Genome-Wide Fetalization of Enhancer Architecture in Heart Disease

Spurrell, Cailyn H., Barozzi, Iros, Mannion, Brandon J., Blow, Matthew J., Fukuda-Yuzawa, Yoko, Afzal, Sarah Y., Akiyama, Jennifer A., Afzal, Veena, Tran, Stella, Plajzer-Frick, Ingrid, Novak, Catherine S., Kato, Momoe, Lee, Elizabeth, Garvin, Tyler H., Pham, Quan T., Harrington, Anne N., Lisgo, Steven, Bristow, James, Cappola, Thomas P., Morley, Michael P., Margulies, Kenneth B., Pennacchio, Len A., Dickel, Diane E., Visel, Axel·2019
DOI 10.1101/591362

Preprint — published as 10.1016/j.celrep.2022.111400

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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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  • The VISTA Cardiac Enhancer Browser contains 2870 cardiac enhancers.

    “This database contains 2870 cardiac enhancers that were also obtained by computational prediction, with some having been functionally validated.”

    From A cis-regulatory-directed pipeline for the identification of genes involved in cardiac development and disease (2021) · cites this paper as [28]

    In “Highly reproducible heart enhancer landscape in healthy individuals” (page unavailable), the paper says the VISTA Enhancer Browser contains 284 human and mouse loci with validated heart activity, not 2,870 cardiac enhancers. It describes those 284 as tested in transgenic mouse assays, rather than saying only some were functionally validated. (LLM, conf=0.90)

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Authors
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.
Publisher
openRxiv
Published
2019-04-01
DOI
10.1101/591362
Cited by
15
References
0
Type
Preprint

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