{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T02:48:17Z","timestamp":1792464497055,"version":"4.5.0"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2014,8]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale<\/jats:underline>\n              :\n            <\/jats:title>\n            <jats:p>\n              The evolutionary conserved\n              <jats:italic>Tbx3<\/jats:italic>\n              \/\n              <jats:italic>Tbx5<\/jats:italic>\n              gene cluster encodes T-box transcription factors that play crucial roles in the development and homeostasis of the cardiac conduction system in human and mouse. Both genes are expressed in overlapping patterns and function in strictly tissue-specific and dose-dependent manners, yet, their regulation is poorly understood.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Objective<\/jats:underline>\n              :\n            <\/jats:title>\n            <jats:p>\n              To analyze the mechanism underlying the complex regulation of the\n              <jats:italic>Tbx3<\/jats:italic>\n              \/\n              <jats:italic>Tbx5<\/jats:italic>\n              cluster.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Methods and Results<\/jats:underline>\n              :\n            <\/jats:title>\n            <jats:p>\n              By probing the 3-dimensional architecture of the\n              <jats:italic>Tbx3\/Tbx5<\/jats:italic>\n              cluster using high-resolution circular chromosome conformation capture sequencing in vivo, we found that its regulatory landscape is in a preformed conformation similar in embryonic heart, limbs, and brain.\n              <jats:italic>Tbx3<\/jats:italic>\n              and its flanking gene desert form a 1 Mbp loop between CCCTC-binding factor (CTCF)-binding sites that is separated from the neighboring\n              <jats:italic>Tbx5<\/jats:italic>\n              loop. However,\n              <jats:italic>Ctcf<\/jats:italic>\n              inactivation did not result in transcriptional regulatory interaction between\n              <jats:italic>Tbx3<\/jats:italic>\n              and\n              <jats:italic>Tbx5<\/jats:italic>\n              . Multiple sites within the\n              <jats:italic>Tbx3<\/jats:italic>\n              locus contact the promoter, including sites corresponding to regions known to contain variations in the human genome influencing conduction. We identified an atrioventricular-specific enhancer and a pan-cardiac enhancer that contact the promoter and each other and synergize to activate transcription in the atrioventricular conduction system.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusions<\/jats:underline>\n              :\n            <\/jats:title>\n            <jats:p>\n              We provide a high-resolution model of the 3-dimensional structure and function of the\n              <jats:italic>Tbx3<\/jats:italic>\n              \/\n              <jats:italic>Tbx5<\/jats:italic>\n              locus and show that the locus is organized in a preformed, permissive structure. The\n              <jats:italic>Tbx3<\/jats:italic>\n              locus forms a CTCF-independent autonomous regulatory domain with multiple combinatorial regulatory elements that control the precise pattern of\n              <jats:italic>Tbx3<\/jats:italic>\n              in the cardiac conduction system.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.115.303591","type":"journal-article","created":{"date-parts":[[2014,6,25]],"date-time":"2014-06-25T02:41:34Z","timestamp":1403664094000},"page":"432-441","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":46,"title":["A Large Permissive Regulatory Domain Exclusively Controls\n            <i>Tbx3<\/i>\n            Expression in the Cardiac Conduction System"],"prefix":"10.1161","volume":"115","author":[{"given":"Jan Hendrik","family":"van Weerd","sequence":"first","affiliation":[{"name":"From the Department of Anatomy, Embryology, and Physiology, Academic Medical Center, Amsterdam, The Netherlands (J.H.v.W., I.B., M.v.d.B., S.S., P.B., V.M.C.); Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands (H.J.G.v.d.W., W.d.L.); Department of Cell Biology, Erasmus MC Rotterdam, Rotterdam, The Netherlands (H.J.G.v.d.W.); and Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (M.G.-V., C.B.-C.,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ileana","family":"Badi","sequence":"additional","affiliation":[{"name":"From the Department of Anatomy, Embryology, and Physiology, Academic Medical Center, Amsterdam, The Netherlands (J.H.v.W., I.B., M.v.d.B., S.S., P.B., V.M.C.); Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands (H.J.G.v.d.W., W.d.L.); Department of Cell Biology, Erasmus MC Rotterdam, Rotterdam, The Netherlands (H.J.G.v.d.W.); and Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (M.G.-V., C.B.-C.,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malou","family":"van den Boogaard","sequence":"additional","affiliation":[{"name":"From the Department of Anatomy, Embryology, and Physiology, Academic Medical Center, Amsterdam, The Netherlands (J.H.v.W., I.B., M.v.d.B., S.S., P.B., V.M.C.); Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands (H.J.G.v.d.W., W.d.L.); Department of Cell Biology, Erasmus MC Rotterdam, Rotterdam, The Netherlands (H.J.G.v.d.W.); and Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (M.G.-V., C.B.-C.,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Stefanovic","sequence":"additional","affiliation":[{"name":"From the Department of Anatomy, Embryology, and Physiology, Academic Medical Center, Amsterdam, The Netherlands (J.H.v.W., I.B., M.v.d.B., S.S., P.B., V.M.C.); Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands (H.J.G.v.d.W., W.d.L.); Department of Cell Biology, Erasmus MC Rotterdam, Rotterdam, The Netherlands (H.J.G.v.d.W.); and Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (M.G.-V., C.B.-C.,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harmen J.G.","family":"van de Werken","sequence":"additional","affiliation":[{"name":"From the Department of Anatomy, Embryology, and Physiology, Academic Medical Center, Amsterdam, The Netherlands (J.H.v.W., I.B., M.v.d.B., S.S., P.B., V.M.C.); Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands (H.J.G.v.d.W., W.d.L.); Department of Cell Biology, Erasmus MC Rotterdam, Rotterdam, The Netherlands (H.J.G.v.d.W.); and Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (M.G.-V., C.B.-C.,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melisa","family":"Gomez-Velazquez","sequence":"additional","affiliation":[{"name":"From the Department of Anatomy, Embryology, and Physiology, Academic Medical Center, Amsterdam, The Netherlands (J.H.v.W., I.B., M.v.d.B., S.S., P.B., V.M.C.); Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands (H.J.G.v.d.W., W.d.L.); Department of Cell Biology, Erasmus MC Rotterdam, Rotterdam, The Netherlands (H.J.G.v.d.W.); and Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (M.G.-V., C.B.-C.,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Badia-Careaga","sequence":"additional","affiliation":[{"name":"From the Department of Anatomy, Embryology, and Physiology, Academic Medical Center, Amsterdam, The Netherlands (J.H.v.W., I.B., M.v.d.B., S.S., P.B., V.M.C.); Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands (H.J.G.v.d.W., W.d.L.); Department of Cell Biology, Erasmus MC Rotterdam, Rotterdam, The Netherlands (H.J.G.v.d.W.); and Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (M.G.-V., C.B.-C.,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Manzanares","sequence":"additional","affiliation":[{"name":"From the Department of Anatomy, Embryology, and Physiology, Academic Medical Center, Amsterdam, The Netherlands (J.H.v.W., I.B., M.v.d.B., S.S., P.B., V.M.C.); Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands (H.J.G.v.d.W., W.d.L.); Department of Cell Biology, Erasmus MC Rotterdam, Rotterdam, The Netherlands (H.J.G.v.d.W.); and Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (M.G.-V., C.B.-C.,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wouter","family":"de Laat","sequence":"additional","affiliation":[{"name":"From the Department of Anatomy, Embryology, and Physiology, Academic Medical Center, Amsterdam, The Netherlands (J.H.v.W., I.B., M.v.d.B., S.S., P.B., V.M.C.); Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands (H.J.G.v.d.W., W.d.L.); Department of Cell Biology, Erasmus MC Rotterdam, Rotterdam, The Netherlands (H.J.G.v.d.W.); and Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (M.G.-V., C.B.-C.,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phil","family":"Barnett","sequence":"additional","affiliation":[{"name":"From the Department of Anatomy, Embryology, and Physiology, Academic Medical Center, Amsterdam, The Netherlands (J.H.v.W., I.B., M.v.d.B., S.S., P.B., V.M.C.); Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands (H.J.G.v.d.W., W.d.L.); Department of Cell Biology, Erasmus MC Rotterdam, Rotterdam, The Netherlands (H.J.G.v.d.W.); and Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (M.G.-V., C.B.-C.,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent M.","family":"Christoffels","sequence":"additional","affiliation":[{"name":"From the Department of Anatomy, Embryology, and Physiology, Academic Medical Center, Amsterdam, The Netherlands (J.H.v.W., I.B., M.v.d.B., S.S., P.B., V.M.C.); Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands (H.J.G.v.d.W., W.d.L.); Department of Cell Biology, Erasmus MC Rotterdam, Rotterdam, The Netherlands (H.J.G.v.d.W.); and Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (M.G.-V., 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