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

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.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Tingwei Guo

    Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, United States
    Competing interests
    No competing interests declared.
  2. Xia Han

    Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, United States
    Competing interests
    No competing interests declared.
  3. Jinzhi He

    Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, United States
    Competing interests
    No competing interests declared.
  4. Jifan Feng

    Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9944-2604
  5. Junjun Jing

    Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5745-5207
  6. Eva Janečková

    Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, United States
    Competing interests
    No competing interests declared.
  7. Jie Lei

    Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, United States
    Competing interests
    No competing interests declared.
  8. Thach-Vu Ho

    Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6293-4739
  9. Jian Xu

    Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, United States
    Competing interests
    Jian Xu, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8162-889X
  10. Yang Chai

    Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, United States
    For correspondence
    ychai@usc.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2477-7247

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.

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).

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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  1. Tingwei Guo
  2. Xia Han
  3. Jinzhi He
  4. Jifan Feng
  5. Junjun Jing
  6. Eva Janečková
  7. Jie Lei
  8. Thach-Vu Ho
  9. Jian Xu
  10. Yang Chai
(2022)
KDM6B interacts with TFDP1 to activate P53 signalling in regulating mouse palatogenesis
eLife 11:e74595.
https://doi.org/10.7554/eLife.74595

Share this article

https://doi.org/10.7554/eLife.74595

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