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Identification of new <jats:italic>FOXF1<\/jats:italic> upstream regulatory elements is critical to explain why frequent non-coding <jats:italic>FOXF1<\/jats:italic> deletions are linked to the disease. Herein, we use multiome single-nuclei RNA and ATAC sequencing of mouse and human patient lungs to identify four conserved endothelial and mesenchymal <jats:italic>FOXF1<\/jats:italic> enhancers. We demonstrate that endothelial <jats:italic>FOXF1<\/jats:italic> enhancers are autoactivated, whereas mesenchymal <jats:italic>FOXF1<\/jats:italic> enhancers are regulated by EBF1 and GLI1. The cell-specificity of <jats:italic>FOXF1<\/jats:italic> enhancers is validated by disrupting these enhancers in mouse embryonic stem cells using CRISPR\/Cpf1 genome editing followed by lineage-tracing of mutant embryonic stem cells in mouse embryos using blastocyst complementation. This study resolves an important clinical question why frequent non-coding <jats:italic>FOXF1<\/jats:italic> deletions that interfere with endothelial and mesenchymal enhancers can lead to the disease.<\/jats:p>","DOI":"10.1038\/s41467-024-49477-6","type":"journal-article","created":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T07:04:08Z","timestamp":1718780648000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Identification of endothelial and mesenchymal FOXF1 enhancers involved in alveolar capillary dysplasia"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3632-4061","authenticated-orcid":false,"given":"Guolun","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingqiang","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5502-9172","authenticated-orcid":false,"given":"Minzhe","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enhong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1668-5174","authenticated-orcid":false,"given":"Jeffrey A.","family":"Whitsett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanya V.","family":"Kalin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3438-2660","authenticated-orcid":false,"given":"Vladimir V.","family":"Kalinichenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,19]]},"reference":[{"key":"49477_CR1","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1242\/dev.098186","volume":"141","author":"M Herriges","year":"2014","unstructured":"Herriges, M. & Morrisey, E. 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