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Although the haploinsufficiency of TBX1 in both mice and humans results in congenital cardiac malformations, little has been elucidated about its upstream regulation. We aimed to explore the transcriptional regulation and dysregulation of <jats:italic>TBX1<\/jats:italic>.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Different <jats:italic>TBX1<\/jats:italic> promoter reporters were constructed. Luciferase assays and electrophoretic mobility shift assays (EMSAs) were used to identify a <jats:italic>cis<\/jats:italic>-regulatory element within the <jats:italic>TBX1<\/jats:italic> promoter region and its <jats:italic>trans<\/jats:italic>-acting factor. The expression of proteins was identified by immunohistochemistry and immunofluorescence. Variants in the <jats:italic>cis<\/jats:italic>-regulatory element were screened in conotruncal defect (CTD) patients. In vitro functional assays were performed to show the effects of the variants found in CTD patients on the transactivation of <jats:italic>TBX1<\/jats:italic>.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We identified a <jats:italic>cis<\/jats:italic>-regulatory element within intron 1 of <jats:italic>TBX1<\/jats:italic> that was found to be responsive to GATA6 (GATA binding protein 6), a transcription factor crucial for cardiogenesis. The expression patterns of GATA6 and TBX1 overlapped in the pharyngeal arches of human embryos. Transfection experiments and EMSA indicated that GATA6 could activate the transcription of <jats:italic>TBX1<\/jats:italic> by directly binding with its GATA <jats:italic>cis<\/jats:italic>-regulatory element in vitro. Furthermore, sequencing analyses of 195 sporadic CTD patients without the 22q11.2 deletion or duplication identified 3 variants (NC_000022.11:g.19756832C\u2009&gt;\u2009G, NC_000022.11:g.19756845C\u2009&gt;\u2009T, and NC_000022.11:g. 19756902G\u2009&gt;\u2009T) in the non-coding <jats:italic>cis<\/jats:italic>-regulatory element of <jats:italic>TBX1<\/jats:italic>. Luciferase assays showed that all 3 variants led to reduced transcription of <jats:italic>TBX1<\/jats:italic> when incubated with GATA6.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our findings showed that <jats:italic>TBX1<\/jats:italic> might be a direct transcriptional target of GATA6, and variants in the non-coding <jats:italic>cis<\/jats:italic>-regulatory element of <jats:italic>TBX1<\/jats:italic> disrupted GATA6-mediated transactivation.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13023-021-01981-4","type":"journal-article","created":{"date-parts":[[2021,7,31]],"date-time":"2021-07-31T21:02:27Z","timestamp":1627765347000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Variants in a cis-regulatory element of TBX1 in conotruncal heart defect patients impair GATA6-mediated transactivation"],"prefix":"10.1186","volume":"16","author":[{"given":"Xuechao","family":"Jiang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sijie","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qihua","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fen","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5716-2284","authenticated-orcid":false,"given":"Yuejuan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,31]]},"reference":[{"issue":"3","key":"1981_CR1","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1038\/85845","volume":"27","author":"LA Jerome","year":"2001","unstructured":"Jerome LA, Papaioannou VE. 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