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Nat Commun. 2016 Oct 5;7:12923. doi: 10.1038/ncomms12923.

Genome-wide compendium and functional assessment of in vivo heart enhancers.

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Functional Genomics Department, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, USA.
Ludwig Institute for Cancer Research, 9500 Gilman Drive, La Jolla, California 92093, USA.
Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, California 92093, USA.
U.S. Department of Energy Joint Genome Institute, Walnut Creek, California 94598, USA.
School of Natural Sciences, University of California, Merced, Merced, California 95343, USA.


Whole-genome sequencing is identifying growing numbers of non-coding variants in human disease studies, but the lack of accurate functional annotations prevents their interpretation. We describe the genome-wide landscape of distant-acting enhancers active in the developing and adult human heart, an organ whose impairment is a predominant cause of mortality and morbidity. Using integrative analysis of >35 epigenomic data sets from mouse and human pre- and postnatal hearts we created a comprehensive reference of >80,000 putative human heart enhancers. To illustrate the importance of enhancers in the regulation of genes involved in heart disease, we deleted the mouse orthologs of two human enhancers near cardiac myosin genes. In both cases, we observe in vivo expression changes and cardiac phenotypes consistent with human heart disease. Our study provides a comprehensive catalogue of human heart enhancers for use in clinical whole-genome sequencing studies and highlights the importance of enhancers for cardiac function.

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