{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T22:59:53Z","timestamp":1790722793748,"version":"4.1.0"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2019,8,30]]},"abstract":"<jats:sec>\n            <jats:title>Rationale:<\/jats:title>\n            <jats:p>\n              The ventricular conduction system (VCS) rapidly propagates electrical impulses through the working myocardium of the ventricles to coordinate chamber contraction. GWAS (Genome-wide association studies) have associated nucleotide polymorphisms, most are located within regulatory intergenic or intronic sequences, with variation in VCS function. Two highly correlated polymorphisms (r\n              <jats:sup>2<\/jats:sup>\n              &gt;0.99) associated with VCS functional variation (rs13165478 and rs13185595) occur 5\u2032 to the gene encoding the basic helix\u2013loop\u2013helix transcription factor HAND1 (heart- and neural crest derivatives-expressed protein 1).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Objective:<\/jats:title>\n            <jats:p>\n              Here, we test the hypothesis that these polymorphisms influence\n              <jats:italic>HAND1<\/jats:italic>\n              transcription thereby influencing VCS development and function.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results:<\/jats:title>\n            <jats:p>\n              We employed transgenic mouse models to identify an enhancer that is sufficient for left ventricle (LV)\n              <jats:italic>cis<\/jats:italic>\n              -regulatory activity. Two evolutionarily conserved GATA transcription factor\n              <jats:italic>cis<\/jats:italic>\n              -binding elements within this enhancer are bound by GATA4 and are necessary for\n              <jats:italic>cis<\/jats:italic>\n              -regulatory activity, as shown by in vitro DNA binding assays. CRISPR (clustered regularly interspaced short palindromic repeats)\/Cas9-mediated deletion of this enhancer dramatically reduces\n              <jats:italic>Hand1<\/jats:italic>\n              expression solely within the LV but does not phenocopy previously published mouse models of cardiac\n              <jats:italic>Hand1<\/jats:italic>\n              loss-of-function. Electrophysiological and morphological analyses reveals that mice homozygous for this deleted enhancer display a morphologically abnormal VCS and a conduction system phenotype consistent with right bundle branch block. Using 1000 Genomes Project data, we identify 3 additional single nucleotide polymorphisms (SNPs), located within the\n              <jats:italic>Hand1<\/jats:italic>\n              LV enhancer, that compose a haplotype with rs13165478 and rs13185595. One of these SNPs, rs10054375, overlaps with a critical GATA\n              <jats:italic>cis<\/jats:italic>\n              -regulatory element within the\n              <jats:italic>Hand1<\/jats:italic>\n              LV enhancer. This SNP, when tested in electrophoretic mobility shift assays, disrupts GATA4 DNA-binding. Modeling 2 of these SNPs in mice causes diminished\n              <jats:italic>Hand1<\/jats:italic>\n              expression and mice present with abnormal VCS function.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              Together, these findings reveal that SNP rs10054375, which is located within a necessary and sufficient LV-specific\n              <jats:italic>Hand1<\/jats:italic>\n              enhancer, exhibits reduces GATA DNA-binding in electrophoretic mobility shift assay, and this enhancer in total, is required for VCS development and function in mice and perhaps humans.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.119.315313","type":"journal-article","created":{"date-parts":[[2019,8,1]],"date-time":"2019-08-01T09:00:16Z","timestamp":1564650016000},"page":"575-589","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":33,"title":["Variation in a Left Ventricle\u2013Specific\n            <i>Hand1<\/i>\n            Enhancer Impairs GATA Transcription Factor Binding and Disrupts Conduction System Development and Function"],"prefix":"10.1161","volume":"125","author":[{"given":"Joshua W.","family":"Vincentz","sequence":"first","affiliation":[{"name":"From the Herman B Wells Center for Pediatric Research, Departments of Pediatrics, Anatomy and Medical and Molecular Genetics, Indiana Medical School, Indianapolis (J.W.V., B.A.F., K.P.T., M.R.L., A.B.F.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beth A.","family":"Firulli","sequence":"additional","affiliation":[{"name":"From the Herman B Wells Center for Pediatric Research, Departments of Pediatrics, Anatomy and Medical and Molecular Genetics, Indiana Medical School, Indianapolis (J.W.V., B.A.F., K.P.T., M.R.L., A.B.F.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin P.","family":"Toolan","sequence":"additional","affiliation":[{"name":"From the Herman B Wells Center for Pediatric Research, Departments of Pediatrics, Anatomy and Medical and Molecular Genetics, Indiana Medical School, Indianapolis (J.W.V., B.A.F., K.P.T., M.R.L., A.B.F.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan E.","family":"Arking","sequence":"additional","affiliation":[{"name":"McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (D.E.A.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nona","family":"Sotoodehnia","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Division of Cardiology, University of Washington, Seattle (N.S.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juyi","family":"Wan","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Krannert Institute of Cardiology, Indianapolis (J.W., P.-S.C.)"},{"name":"Department of Cardiothoracic Surgery, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, China (J.W.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng-Sheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Krannert Institute of Cardiology, Indianapolis (J.W., P.-S.C.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corrie","family":"de Gier-de Vries","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Academic Medical Center, University of Amsterdam, the Netherlands (C.d.G.V., V.M.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent M.","family":"Christoffels","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Academic Medical Center, University of Amsterdam, the Netherlands (C.d.G.V., V.M.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Rubart-von der Lohe","sequence":"additional","affiliation":[{"name":"From the Herman B Wells Center for Pediatric Research, Departments of Pediatrics, Anatomy and Medical and Molecular Genetics, Indiana Medical School, Indianapolis (J.W.V., B.A.F., K.P.T., M.R.L., A.B.F.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony B.","family":"Firulli","sequence":"additional","affiliation":[{"name":"From the Herman B Wells Center for Pediatric Research, Departments of Pediatrics, Anatomy and Medical and Molecular Genetics, Indiana Medical School, Indianapolis (J.W.V., B.A.F., K.P.T., M.R.L., 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