{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T07:04:06Z","timestamp":1763535846428,"version":"3.41.2"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,4,8]],"date-time":"2021-04-08T00:00:00Z","timestamp":1617840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011781","name":"Shriners Hospitals for Children","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011781","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Disruption of <jats:italic>FOXF2<\/jats:italic>, encoding a member of the Forkhead family transcription factors, has been associated with cleft palate in humans and mice. <jats:italic>FOXF2<\/jats:italic> is located in a conserved gene cluster containing <jats:italic>FOXQ1<\/jats:italic>, <jats:italic>FOXF2<\/jats:italic>, and <jats:italic>FOXC1<\/jats:italic>. We found that expression of <jats:italic>Foxq1<\/jats:italic> is dramatically upregulated in the embryonic palatal mesenchyme in <jats:italic>Foxf2<\/jats:italic><jats:sup>\u2013\/\u2013<\/jats:sup> mouse embryos. We show here that the <jats:italic>Foxf2<\/jats:italic> promoter-deletion mutation caused dramatically increased expression of the <jats:italic>cis<\/jats:italic>-linked <jats:italic>Foxq1<\/jats:italic> allele but had little effect on the <jats:italic>Foxq1<\/jats:italic> allele in <jats:italic>trans<\/jats:italic>. We analyzed effects of the <jats:italic>Foxf2<\/jats:italic> mutation on the expression of other neighboring genes and compared those effects with the chromatin domain structure and recently identified enhancer-promoter associations as well as H3K27ac ChIP-seq data. We show that the <jats:italic>Foxf2<\/jats:italic> mutation resulted in significantly increased expression of the <jats:italic>Foxq1<\/jats:italic> and <jats:italic>Exoc2<\/jats:italic> genes located in the same topologically associated domain with <jats:italic>Foxf2<\/jats:italic> but not the expression of the <jats:italic>Foxc1<\/jats:italic> and <jats:italic>Gmds<\/jats:italic> genes located in the adjacent chromatin domain. We inactivated the <jats:italic>Foxq1<\/jats:italic> gene in mice homozygous for a <jats:italic>Foxf2<\/jats:italic> conditional allele using CRISPR genome editing and generated <jats:italic>(Foxf2\/Foxq1)<jats:sup>+\/\u2013<\/jats:sup><\/jats:italic> mice with loss-of-function mutations in <jats:italic>Foxf2<\/jats:italic> and <jats:italic>Foxq1<\/jats:italic> in <jats:italic>cis<\/jats:italic>. Whereas the <jats:italic>(Foxf2\/Foxq1)<jats:sup>\u2013\/\u2013<\/jats:sup><\/jats:italic> mice exhibited cleft palate at birth similar as in the <jats:italic>Foxf2<\/jats:italic><jats:sup>\u2013\/\u2013<\/jats:sup> mice, systematic expression analyses of a large number of Foxf2-dependent genes revealed that the (<jats:italic>Foxf2<\/jats:italic>\/<jats:italic>Foxq1)<jats:sup>\u2013\/\u2013<\/jats:sup><\/jats:italic> embryos exhibited distinct effects on the domain-specific expression of several important genes, including <jats:italic>Foxf1<\/jats:italic>, <jats:italic>Shox2<\/jats:italic>, and <jats:italic>Spon1<\/jats:italic>, in the developing palatal shelves compared with <jats:italic>Foxf2<\/jats:italic><jats:sup>\u2013\/\u2013<\/jats:sup> embryos. These results identify a novel <jats:italic>cis<\/jats:italic>-regulatory effect of the <jats:italic>Foxf2<\/jats:italic> mutation and demonstrate that <jats:italic>cis-<\/jats:italic>regulation of <jats:italic>Foxq1<\/jats:italic> contributed to alterations in palatal gene expression in <jats:italic>Foxf2<\/jats:italic><jats:sup>\u2013\/\u2013<\/jats:sup> embryos. These results have important implications for interpretation of results and mechanisms from studies of promoter- or gene-deletion alleles. In addition, the unique mouse lines generated in this study provide a valuable resource for understanding the cross-regulation and combinatorial functions of the <jats:italic>Foxf2<\/jats:italic> and <jats:italic>Foxq1<\/jats:italic> genes in development and disease.<\/jats:p>","DOI":"10.3389\/fcell.2021.665109","type":"journal-article","created":{"date-parts":[[2021,4,8]],"date-time":"2021-04-08T04:55:00Z","timestamp":1617857700000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Cis-Repression of Foxq1 Expression Affects Foxf2-Mediated Gene Expression in Palate Development"],"prefix":"10.3389","volume":"9","author":[{"given":"Jingyue","family":"Xu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Han","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Lan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rulang","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,4,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7563","DOI":"10.1074\/jbc.m114.609487","article-title":"Forkhead box F2 regulation of platelet-derived growth factor and myocardin\/serum response factor signaling is essential for intestinal development.","volume":"290","author":"Bolte","year":"2015","journal-title":"J. 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