KDM6B interacts with TFDP1 to activate P53 signalling in regulating mouse palatogenesis
- University of Southern California, United States
Abstract
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, a 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.
Data availability
Sequencing data have been deposited in GEO under accession code GSE175383.
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KDM6B interacts with TFDP1 to activate P53 signalling in regulating mouse palatogenesisNCBI Gene Expression Omnibus, GSE175383.
Article and author information
Author details
Funding
National Institutes of Health (R01 DE012711)
- Yang Chai
National Institutes of Health (R01 DE022503)
- Yang Chai
National Institutes of Health (U01 DE028729)
- Yang Chai
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Marianne E Bronner, California Institute of Technology, United States
Ethics
Animal experimentation: All mouse studies were conducted with protocols approved by the Department of Animal Resources and the Institutional Animal Care and Use Committee (IACUC) of the University of Southern California (Protocols 9320 and 20299).
Version history
- Received: October 9, 2021
- Preprint posted: October 14, 2021 (view preprint)
- Accepted: February 24, 2022
- Accepted Manuscript published: February 25, 2022 (version 1)
- Version of Record published: April 13, 2022 (version 2)
Copyright
© 2022, Guo et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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KDM6B interacts with TFDP1 to activate P53 signalling in regulating mouse palatogenesis
eLife 11:e74595.
https://doi.org/10.7554/eLife.74595
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