Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, United States.
Elife. 2022 Feb 25;11:e74595. doi: 10.7554/eLife.74595.
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 , an H3K27me3 demethylase, in regulating mouse embryonic development. Our study shows that plays an essential role in cranial neural crest development, and loss of 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 is antagonistically controlled by , and in cranial neural crest cells. More importantly, without , the transcription factor TFDP1, which normally binds to the promoter of , cannot activate expression in palatal mesenchymal cells. Furthermore, the function of in activating in these cells cannot be compensated for by the closely related histone demethylase . 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 expression, and further provide mechanistic insights into the epigenetic regulatory network during organogenesis.
表观遗传调控在疾病和发育中发挥着广泛的作用。表观遗传调控的破坏不仅会增加癌症的风险，还会导致各种发育缺陷。然而，在神经嵴命运决定和分化过程中，表观遗传变化如何导致组织特异性反应的问题仍未得到充分研究。我们使用腭发生作为模型，揭示了 H3K27me3 去甲基酶在调节小鼠胚胎发育中的功能意义。我们的研究表明，在颅神经嵴发育中，扮演着重要的角色，的缺失扰乱了 P53 途径介导的活性，导致小鼠完全腭裂，同时伴有细胞增殖和分化缺陷。此外，H3K27me3 在 启动子上的活性受到 和 的拮抗控制。更重要的是，没有 ，通常结合在 启动子上的转录因子 TFDP1 就不能在腭间充质细胞中激活 的表达。此外，在这些细胞中， 激活 的功能不能被密切相关的组蛋白去甲基酶 所补偿。总的来说，我们的研究结果强调了表观遗传调控因子 KDM6B 的重要作用，以及它如何与 TFDP1 特异性相互作用，从而在调节 的表达中实现其功能特异性，并进一步为器官发生过程中的表观遗传调控网络提供了机制上的见解。
