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Therefore, to comprehensively characterize these transcriptional regulations, day-to-day transcriptomic profiles were generated throughout the directed cardiac differentiation, starting from three distinct human- induced pluripotent stem cell lines from healthy donors (32 days). We applied an expression-based correlation score to the chronological expression profiles of the TF genes, and clustered them into 12 sequential gene expression waves. We then identified a regulatory network of more than 23,000 activation and inhibition links between 216 TFs. Within this network, we observed previously unknown inferred transcriptional activations linking IRX3 and IRX5 TFs to three master cardiac TFs: GATA4, NKX2-5 and TBX5. Luciferase and co-immunoprecipitation assays demonstrated that these five TFs could (1) activate each other\u2019s expression; (2) interact physically as multiprotein complexes; and (3) together, finely regulate the expression of SCN5A, encoding the major cardiac sodium channel. Altogether, these results unveiled thousands of interactions between TFs, generating multiple robust hypotheses governing human cardiac development.<\/jats:p>","DOI":"10.3390\/cells11233915","type":"journal-article","created":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T04:40:09Z","timestamp":1670215209000},"page":"3915","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Deciphering Transcriptional Networks during Human Cardiac Development"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9036-1496","authenticated-orcid":false,"given":"Robin","family":"Canac","sequence":"first","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019institut du thorax, F-44000 Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7485-8200","authenticated-orcid":false,"given":"Bastien","family":"Cimarosti","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019institut du thorax, F-44000 Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2915-2812","authenticated-orcid":false,"given":"Aurore","family":"Girardeau","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019institut du thorax, F-44000 Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginie","family":"Forest","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019institut du thorax, F-44000 Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Olchesqui","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019institut du thorax, F-44000 Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremie","family":"Poschmann","sequence":"additional","affiliation":[{"name":"INSERM, Nantes Universit\u00e9, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, F-44000 Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Redon","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019institut du thorax, F-44000 Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5330-2008","authenticated-orcid":false,"given":"Patricia","family":"Lemarchand","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019institut du thorax, F-44000 Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5231-6555","authenticated-orcid":false,"given":"Nathalie","family":"Gaborit","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019institut du thorax, F-44000 Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillaume","family":"Lamirault","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l\u2019institut du thorax, F-44000 Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1038\/s41569-018-0086-9","article-title":"The Deployment of Cell Lineages That Form the Mammalian Heart","volume":"15","author":"Meilhac","year":"2018","journal-title":"Nat. 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