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Epigenetic regulation plays extensive roles in diseases and development. 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  Kdm6b , an H3K27me3 demethylase, in regulating mouse embryonic development. Our study shows that  Kdm6b  plays an essential role in cranial neural crest development, and loss of  Kdm6b  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  Trp53  is antagonistically controlled by  Kdm6b , and  Ezh2  in cranial neural crest cells. More importantly, without  Kdm6b , the transcription factor TFDP1, which normally binds to the promoter of  Trp53 , cannot activate  Trp53  expression in palatal mesenchymal cells. Furthermore, the function of  Kdm6b  in activating  Trp53  in these cells cannot be compensated for by the closely related histone demethylase  Kdm6a . 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  Trp53  expression, and further provide mechanistic insights into the epigenetic regulatory network during organogenesis.

KDM6B interacts with TFDP1 to activate P53 signaling in regulating mouse palatogenesis