{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T02:48:58Z","timestamp":1791946138735,"version":"4.3.4"},"reference-count":62,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","funder":[{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","award":["40-00812-98-12086"],"award-info":[{"award-number":["40-00812-98-12086"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002996","name":"Hartstichting","doi-asserted-by":"publisher","award":["2013T091"],"award-info":[{"award-number":["2013T091"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001674","name":"Fondation Leducq","doi-asserted-by":"publisher","award":["14CVD01"],"award-info":[{"award-number":["14CVD01"]}],"id":[{"id":"10.13039\/501100001674","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche Medicale","doi-asserted-by":"crossref","award":["PBR201810007613"],"award-info":[{"award-number":["PBR201810007613"]}],"id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["HL064658"],"award-info":[{"award-number":["HL064658"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["HL136182"],"award-info":[{"award-number":["HL136182"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2020,12,4]]},"abstract":"<jats:sec>\n            <jats:title>Rationale:<\/jats:title>\n            <jats:p>The development and function of the pacemaker cardiomyocytes of the sinoatrial node (SAN), the leading pacemaker of the heart, are tightly controlled by a conserved network of transcription factors, including TBX3 (T-box transcription factor 3), ISL1 (ISL LIM homeobox 1), and SHOX2 (short stature homeobox 2). Yet, the regulatory DNA elements (REs) controlling target gene expression in the SAN pacemaker cells have remained undefined.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Objective:<\/jats:title>\n            <jats:p>Identification of the regulatory landscape of human SAN-like pacemaker cells and functional assessment of SAN-specific REs potentially involved in pacemaker cell gene regulation.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results:<\/jats:title>\n            <jats:p>\n              We performed Assay for Transposase-Accessible Chromatin using sequencing on human pluripotent stem cell\u2013derived SAN-like pacemaker cells and ventricle-like cells and identified thousands of putative REs specific for either human cell type. We validated pacemaker cell\u2013specific elements in the\n              <jats:italic>SHOX2<\/jats:italic>\n              and\n              <jats:italic>TBX3<\/jats:italic>\n              loci. CRISPR-mediated homozygous deletion of the mouse ortholog of a noncoding region with candidate pacemaker-specific REs in the\n              <jats:italic>SHOX2<\/jats:italic>\n              locus resulted in selective loss of\n              <jats:italic>Shox2<\/jats:italic>\n              expression from the developing SAN and embryonic lethality. Putative pacemaker-specific REs were identified up to 1 Mbp upstream of\n              <jats:italic>TBX3<\/jats:italic>\n              in a region close to\n              <jats:italic>MED13L<\/jats:italic>\n              harboring variants associated with heart rate recovery after exercise. The orthologous region was deleted in mice, which resulted in selective loss of expression of\n              <jats:italic>Tbx3<\/jats:italic>\n              from the SAN and (cardiac) ganglia and in neonatal lethality. Expression of\n              <jats:italic>Tbx3<\/jats:italic>\n              was maintained in other tissues including the atrioventricular conduction system, lungs, and liver. Heterozygous adult mice showed increased SAN recovery times after pacing. The human REs harboring the associated variants robustly drove expression in the SAN of transgenic mouse embryos.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              We provided a genome-wide collection of candidate human pacemaker-specific REs, including the loci of\n              <jats:italic>SHOX2<\/jats:italic>\n              ,\n              <jats:italic>TBX3<\/jats:italic>\n              , and\n              <jats:italic>ISL1<\/jats:italic>\n              , and identified a link between human genetic variants influencing heart rate recovery after exercise and a variant RE with highly conserved function, driving SAN expression of\n              <jats:italic>TBX3<\/jats:italic>\n              .\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.120.317054","type":"journal-article","created":{"date-parts":[[2020,10,12]],"date-time":"2020-10-12T09:00:12Z","timestamp":1602493212000},"page":"1522-1535","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":40,"title":["Genome-Wide Analysis Identifies an Essential Human TBX3 Pacemaker Enhancer"],"prefix":"10.1161","volume":"127","author":[{"given":"Vincent W.W.","family":"van Eif","sequence":"first","affiliation":[{"name":"Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam (V.W.W.v.E., F.M.B., K.v.D., R.A.M., V.W., C.d.G.-d.V., I.B.H., A.O.V., B.J.B., V.M.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie I.","family":"Protze","sequence":"additional","affiliation":[{"name":"McEwen Stem Cell Institute, University Health Network and the Department of Molecular Genetics, University of Toronto 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