title: Genome-wide compendium and functional assessment of in vivo heart enhancers.
abstract: 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.
authors.affiliation: Functional Genomics Department, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, USA.
authors.forename: Diane E
authors.identifier: 0000-0001-5497-6824
authors.initials: DE
authors.lastname: Dickel
authors.affiliation: Functional Genomics Department, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, USA.
authors.forename: Iros
authors.initials: I
authors.lastname: Barozzi
authors.affiliation: Functional Genomics Department, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, USA.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Functional Genomics Department, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, USA.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Fukuda-Yuzawa
authors.affiliation: Functional Genomics Department, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, USA.
authors.forename: Marco
authors.identifier: 0000-0002-1969-2313
authors.initials: M
authors.lastname: Osterwalder
authors.affiliation: Functional Genomics Department, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, USA.
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Mannion
authors.affiliation: Functional Genomics Department, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, USA.
authors.forename: Dalit
authors.initials: D
authors.lastname: May
authors.affiliation: Functional Genomics Department, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, USA.
authors.forename: Cailyn H
authors.initials: CH
authors.lastname: Spurrell
authors.affiliation: Functional Genomics Department, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, USA.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Plajzer-Frick
authors.affiliation: Functional Genomics Department, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, USA.
authors.forename: Catherine S
authors.initials: CS
authors.lastname: Pickle
authors.affiliation: Functional Genomics Department, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Lee
authors.affiliation: Functional Genomics Department, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, USA.
authors.forename: Tyler H
authors.initials: TH
authors.lastname: Garvin
authors.affiliation: Functional Genomics Department, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, USA.
authors.forename: Momoe
authors.initials: M
authors.lastname: Kato
authors.affiliation: Functional Genomics Department, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Akiyama
authors.affiliation: Functional Genomics Department, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, USA.
authors.forename: Veena
authors.initials: V
authors.lastname: Afzal
authors.affiliation: Ludwig Institute for Cancer Research, 9500 Gilman Drive, La Jolla, California 92093, USA.
authors.forename: Ah Young
authors.initials: AY
authors.lastname: Lee
authors.affiliation: Ludwig Institute for Cancer Research, 9500 Gilman Drive, La Jolla, California 92093, USA.
authors.forename: David U
authors.initials: DU
authors.lastname: Gorkin
authors.affiliation: 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.
authors.forename: Bing
authors.initials: B
authors.lastname: Ren
authors.affiliation: Functional Genomics Department, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, USA.|U.S. Department of Energy Joint Genome Institute, Walnut Creek, California 94598, USA.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Rubin
authors.affiliation: Functional Genomics Department, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, 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.
authors.forename: Axel
authors.identifier: 0000-0002-4130-7784
authors.initials: A
authors.lastname: Visel
authors.affiliation: Functional Genomics Department, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, USA.|U.S. Department of Energy Joint Genome Institute, Walnut Creek, California 94598, USA.
authors.forename: Len A
authors.initials: LA
authors.lastname: Pennacchio
mesh_terms: D000818:Animals; D004452:Echocardiography; D004742:Enhancer Elements, Genetic; D057890:Epigenomics; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018507:Gene Expression Regulation, Developmental; D015894:Genome, Human; D006321:Heart / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D010641:Phenotype
chemical_list: D006657:Histones