{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T19:22:33Z","timestamp":1790018553334,"version":"4.0.1"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2021,5,6]],"date-time":"2021-05-06T00:00:00Z","timestamp":1620259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"crossref","award":["2017YFA0103700"],"award-info":[{"award-number":["2017YFA0103700"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["91949111"],"award-info":[{"award-number":["91949111"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81770257"],"award-info":[{"award-number":["81770257"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81970223"],"award-info":[{"award-number":["81970223"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004608","name":"Natural Science Foundation of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20201409"],"award-info":[{"award-number":["BK20201409"]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Top Six Talents in Jiangsu Province","award":["SWYY-081"],"award-info":[{"award-number":["SWYY-081"]}]},{"name":"Medical Science and Technology Projects of Jiangsu Province","award":["BE2016633"],"award-info":[{"award-number":["BE2016633"]}]},{"name":"Key Talents Project of Jiangsu Province","award":["WSW-108"],"award-info":[{"award-number":["WSW-108"]}]},{"name":"Key Talents Project of Jiangsu Province","award":["FRC-201754"],"award-info":[{"award-number":["FRC-201754"]}]},{"name":"Key Talents Project of Jiangsu Province","award":["CXTDJS003"],"award-info":[{"award-number":["CXTDJS003"]}]},{"DOI":"10.13039\/501100003787","name":"Natural Science Foundation of Hebei Province","doi-asserted-by":"publisher","award":["C2020405008"],"award-info":[{"award-number":["C2020405008"]}],"id":[{"id":"10.13039\/501100003787","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Open Project of Hubei Key Laboratory of Embryonic Stem Cell Research","award":["2020ESOF001"],"award-info":[{"award-number":["2020ESOF001"]}]},{"name":"Jiangsu Province\u2019s Key Discipline\/Laboratory of Medicine","award":["XK201118"],"award-info":[{"award-number":["XK201118"]}]},{"name":"National Center for International Research","award":["2017B01012"],"award-info":[{"award-number":["2017B01012"]}]},{"name":"Introduction Project of Clinical Medicine Expert Team for Suzhou","award":["SZYJTD201704"],"award-info":[{"award-number":["SZYJTD201704"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,2,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Congenital heart disease (CHD) frequently occurs in newborns due to abnormal formation of the heart or major blood vessels. Mutations in the GATA4 gene, which encodes GATA binding protein 4, are responsible for atrial septal defect (ASD), a common CHD. This study aims to gain insights into the molecular mechanisms of CHD using human-induced pluripotent stem cells (iPSCs) from a family cohort with ASD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Patient-specific iPSCs possess the same genetic information as the donor and can differentiate into various cell types from all three germ layers in vitro, thus presenting a promising approach for disease modelling and molecular mechanism research. Here, we generated a patient-specific iPSC line (iPSC-G4T280M) from a family cohort carrying a hereditary ASD mutation in GATA4 gene (T280M), as well as a human embryonic stem cell line (ESC-G4T280M) carrying the isogenic T280M mutation using the CRISPR\/Cas9 genome editing method. The GATA4-mutant iPSCs and ESCs were then differentiated into cardiomyocytes (CMs) to model GATA4 mutation-associated ASD. We observed an obvious defect in cell proliferation in cardiomyocytes derived from both GATA4T280M-mutant iPSCs (iPSC-G4T280M-CMs) and ESCs (ESC-G4T280M-CMs), while the impaired proliferation ability of iPSC-G4T280M-CMs could be restored by gene correction. Integrated analysis of RNA-Seq and ChIP-Seq data indicated that FGF16 is a direct target of wild-type GATA4. However, the T280M mutation obstructed GATA4 occupancy at the FGF16 promoter region, leading to impaired activation of FGF16 transcription. Overexpression of FGF16 in GATA4-mutant cardiomyocytes rescued the cell proliferation defect. The direct relationship between GATA4T280M and ASD was demonstrated in a human iPSC model for the first time.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In summary, our study revealed the molecular mechanism of the GATA4T280M mutation in ASD. Understanding the roles of the GATA4-FGF16 axis in iPSC-CMs will shed light on heart development and provide novel insights for the treatment of ASD and other CHD disorders.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvab154","type":"journal-article","created":{"date-parts":[[2021,5,4]],"date-time":"2021-05-04T07:22:08Z","timestamp":1620112928000},"page":"859-871","source":"Crossref","is-referenced-by-count":47,"title":["Patient-specific iPSC-derived cardiomyocytes reveal abnormal regulation of\n                    <i>FGF16<\/i>\n                    in a familial atrial septal defect"],"prefix":"10.1093","volume":"118","author":[{"given":"Lingqun","family":"Ye","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"You","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen-Ao","family":"Zhao","sequence":"additional","affiliation":[{"name":"Institute of Microcirculation & Department of Pathophysiology of Basic Medical College, Hebei North University, Zhangjiakou 075000, China"},{"name":"Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Zhangjiakou 075000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Ni","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9823-9620","authenticated-orcid":false,"given":"Xing","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongming","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200432, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Ming","family":"Tang","sequence":"additional","affiliation":[{"name":"Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medicine Science, Hubei University of Medicine, Shiyan 442000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Chen","sequence":"additional","affiliation":[{"name":"Central Lab, the Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi 214002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenya","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Lei","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0068-8429","authenticated-orcid":false,"given":"Shijun","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,5,6]]},"reference":[{"key":"2022022108494914400_cvab154-B1","doi-asserted-by":"crossref","first-page":"e56","DOI":"10.1161\/CIR.0000000000000659","article-title":"Heart disease and stroke statistics-2019 update: a report from the American Heart Association","volume":"139","author":"Benjamin","year":"2019","journal-title":"Circulation"},{"key":"2022022108494914400_cvab154-B2","doi-asserted-by":"crossref","first-page":"e006906","DOI":"10.1161\/JAHA.117.006906","article-title":"Advances in the understanding of the genetic determinants of congenital heart disease and their impact on clinical outcomes","volume":"7","author":"Russell","year":"2018","journal-title":"J Am Heart 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