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Disruption of epigenetic regulation not only increases the risk of cancer, but can also cause various developmental defects. However, the question of how epigenetic changes lead to tissue-specific responses during neural crest fate determination and differentiation remains understudied. Using palatogenesis as a model, we reveal the functional significance of\n                    <jats:italic>Kdm6b<\/jats:italic>\n                    , an H3K27me3 demethylase, in regulating mouse embryonic development. Our study shows that\n                    <jats:italic>Kdm6b<\/jats:italic>\n                    plays an essential role in cranial neural crest development, and loss of\n                    <jats:italic>Kdm6b<\/jats:italic>\n                    disturbs P53 pathway-mediated activity, leading to complete cleft palate along with cell proliferation and differentiation defects in mice. Furthermore, activity of H3K27me3 on the promoter of\n                    <jats:italic>Trp53<\/jats:italic>\n                    is antagonistically controlled by\n                    <jats:italic>Kdm6b<\/jats:italic>\n                    , and\n                    <jats:italic>Ezh2<\/jats:italic>\n                    in cranial neural crest cells. More importantly, without\n                    <jats:italic>Kdm6b<\/jats:italic>\n                    , the transcription factor TFDP1, which normally binds to the promoter of\n                    <jats:italic>Trp53<\/jats:italic>\n                    , cannot activate\n                    <jats:italic>Trp53<\/jats:italic>\n                    expression in palatal mesenchymal cells. Furthermore, the function of\n                    <jats:italic>Kdm6b<\/jats:italic>\n                    in activating\n                    <jats:italic>Trp53<\/jats:italic>\n                    in these cells cannot be compensated for by the closely related histone demethylase\n                    <jats:italic>Kdm6a<\/jats:italic>\n                    . Collectively, our results highlight the important role of the epigenetic regulator KDM6B and how it specifically interacts with TFDP1 to achieve its functional specificity in regulating\n                    <jats:italic>Trp53<\/jats:italic>\n                    expression, and further provide mechanistic insights into the epigenetic regulatory network during organogenesis.\n                  <\/jats:p>","DOI":"10.7554\/elife.74595","type":"journal-article","created":{"date-parts":[[2022,2,25]],"date-time":"2022-02-25T08:00:47Z","timestamp":1645776047000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.74595","source":"Crossref","is-referenced-by-count":21,"title":["KDM6B interacts with TFDP1 to activate P53 signaling in regulating mouse palatogenesis"],"prefix":"10.7554","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4089-1867","authenticated-orcid":true,"given":"Tingwei","family":"Guo","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03taz7m60","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California","place":["Los Angeles, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Han","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03taz7m60","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California","place":["Los Angeles, United 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