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However, how the expression of\n                    <jats:italic>SRY<\/jats:italic>\n                    is regulated remains elusive. Here, we demonstrate that a conserved steroidogenic factor-1 (SF-1)\/NR5A1 binding enhancer is required for appropriate\n                    <jats:italic>SRY<\/jats:italic>\n                    expression to initiate testis-determination in humans. Comparative sequence analysis of\n                    <jats:italic>SRY<\/jats:italic>\n                    5\u2019 regions in mammals identified an evolutionary conserved SF-1\/NR5A1-binding motif within a 250\u2009bp region of open chromatin located 5 kilobases upstream of the\n                    <jats:italic>SRY<\/jats:italic>\n                    transcription start site. Genomic analysis of 46,XY individuals with disrupted testis-determination, including a large multigenerational family, identified unique single-base substitutions of highly conserved residues within the SF-1\/NR5A1-binding element. In silico modelling and in vitro assays demonstrate the enhancer properties of the NR5A1 motif. Deletion of this hemizygous element by genome-editing, in a novel in vitro cellular model recapitulating human Sertoli cell formation, resulted in a significant reduction in expression of\n                    <jats:italic>SRY<\/jats:italic>\n                    . Therefore, human NR5A1 acts as a regulatory switch between testis and ovary development by upregulating\n                    <jats:italic>SRY<\/jats:italic>\n                    expression, a role that may predate the eutherian radiation. We show that disruption of an enhancer can phenocopy variants in the coding regions of\n                    <jats:italic>SRY<\/jats:italic>\n                    that cause human testis dysgenesis. Since disease causing variants in enhancers are currently rare, the regulation of gene expression in testis-determination offers a paradigm to define enhancer activity in a key developmental process.\n                  <\/jats:p>","DOI":"10.1038\/s41467-024-47162-2","type":"journal-article","created":{"date-parts":[[2024,3,30]],"date-time":"2024-03-30T13:01:58Z","timestamp":1711803718000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["A conserved NR5A1-responsive enhancer regulates SRY in testis-determination"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8536-9039","authenticated-orcid":false,"given":"Denis","family":"Houzelstein","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6968-0110","authenticated-orcid":false,"given":"Caroline","family":"Eozenou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5432-9747","authenticated-orcid":false,"given":"Carlos F.","family":"Lagos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0499-1724","authenticated-orcid":false,"given":"Ma\u00ebva","family":"Elzaiat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joelle","family":"Bignon-Topalovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2523-499X","authenticated-orcid":false,"given":"Inma","family":"Gonzalez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4946-698X","authenticated-orcid":false,"given":"Vincent","family":"Laville","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laur\u00e8ne","family":"Schlick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Somboon","family":"Wankanit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7394-6345","authenticated-orcid":false,"given":"Prochi","family":"Madon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jyotsna","family":"Kirtane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0480-6226","authenticated-orcid":false,"given":"Arundhati","family":"Athalye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8274-7241","authenticated-orcid":false,"given":"Federica","family":"Buonocore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6328-0703","authenticated-orcid":false,"given":"St\u00e9phanie","family":"Bigou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3346-5029","authenticated-orcid":false,"given":"Gerard S.","family":"Conway","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8262-5642","authenticated-orcid":false,"given":"Delphine","family":"Bohl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8787-6272","authenticated-orcid":false,"given":"John C.","family":"Achermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anu","family":"Bashamboo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6582-1801","authenticated-orcid":false,"given":"Ken","family":"McElreavey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,30]]},"reference":[{"key":"47162_CR1","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1038\/nrg.2017.60","volume":"18","author":"B Capel","year":"2017","unstructured":"Capel, B. 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