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Peer-reviewedCC BY-NC-NDEpigenetics & chromatin

ASH2L-mediated H3K4me3 methylation governs palatal development by regulating WNT5B.

  • Zhichen Ling1,2,3,4,5
  • Xueqin Zhu1,2,3,4,5
  • Xinyi Tan1,2,3,4,5
  • Zhangke Ma1,2,3,4,5
  • Furong Xie6,7,8,9,10
  • Jun Wang11,12,13,14,15
15 affiliations
  1. 1Department of Pediatric Dentistry, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  2. 2College of Stomatology, Shanghai Jiao Tong University, Shanghai, China.
  3. 3National Center for Stomatology, Shanghai, China.
  4. 4National Clinical Research Center for Oral Diseases, Shanghai, China.
  5. 5Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.
  6. 6Department of Pediatric Dentistry, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  7. 7College of Stomatology, Shanghai Jiao Tong University, Shanghai, China. [email protected].
  8. 8National Center for Stomatology, Shanghai, China. [email protected].
  9. 9National Clinical Research Center for Oral Diseases, Shanghai, China. [email protected].
  10. 10Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China. [email protected].
  11. 11Department of Pediatric Dentistry, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  12. 12College of Stomatology, Shanghai Jiao Tong University, Shanghai, China. [email protected].
  13. 13National Center for Stomatology, Shanghai, China. [email protected].
  14. 14National Clinical Research Center for Oral Diseases, Shanghai, China. [email protected].
  15. 15Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China. [email protected].
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Abstract

Background

Orofacial clefts, particularly cleft palate, are among the most common congenital anomalies, imposing substantial functional impairment and psychosocial burden on affected individuals. Emerging evidence implicates epigenetic modifications, especially histone lysine methylation, as critical regulators of embryonic development, yet their precise roles in palatogenesis remain poorly defined. The H3K4 methyltransferase complexes, which require the core subunit ASH2L for full enzymatic activity, govern transcriptional activation during development; however, whether ASH2L-mediated H3K4me3 deposition contributes to palatal morphogenesis is unknown.Results

Here, we show that conditional deletion of Ash2l in Six2-positive palatal mesenchymal cells results in complete cleft palate in mice. Multi-omics analyses (RNA-seq and CUT&Tag-seq) reveal that Ash2l loss causes genome-wide reduction of H3K4me3 enrichment at key developmental genes, most notably Wnt5b, leading to their transcriptional downregulation. Functionally, Ash2l deficiency impairs proliferation and osteogenic differentiation of palatal mesenchymal cells, resulting in stunted palatal shelf growth and disrupted osteogenesis. Pharmacological activation of WNT signaling downstream of Wnt5b partially rescues these cellular defects, confirming the functional relevance of this axis.Conclusion

These findings establish ASH2L-mediated H3K4me3 as a critical epigenetic regulator of palatal development through WNT5B modulation, and identify potential therapeutic targets for cleft palate.

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Cite

BibTeXRIS
BibTeX
@article{ling2026ash2lmediated,
  title = {{ASH2L-mediated H3K4me3 methylation governs palatal development by regulating WNT5B.}},
  author = {Zhichen Ling and Xueqin Zhu and Xinyi Tan and Zhangke Ma and Furong Xie and Jun Wang},
  journal = {Epigenetics \& chromatin},
  year = {2026},
  month = jul,
  doi = {10.1186/s13072-026-00690-1},
  url = {https://europepmc.org/article/MED/42902390},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - ASH2L-mediated H3K4me3 methylation governs palatal development by regulating WNT5B.
AU  - Zhichen Ling
AU  - Xueqin Zhu
AU  - Xinyi Tan
AU  - Zhangke Ma
AU  - Furong Xie
AU  - Jun Wang
PY  - 2026
DA  - 2026/07/01
JO  - Epigenetics & chromatin
DO  - 10.1186/s13072-026-00690-1
UR  - https://europepmc.org/article/MED/42902390
AB  - Background  Orofacial clefts, particularly cleft palate, are among the most common congenital anomalies, imposing substantial functional impairment and psychosocial burden on affected individuals. Emerging evidence implicates epigenetic modifications, especially histone lysine methylation, as critical regulators of embryonic development, yet their precise roles in palatogenesis remain poorly defined. The H3K4 methyltransferase complexes, which require the core subunit ASH2L for full enzymatic activity, govern transcriptional activation during development; however, whether ASH2L-mediated H3K4me3 deposition contributes to palatal morphogenesis is unknown.Results  Here, we show that conditional deletion of Ash2l in Six2-positive palatal mesenchymal cells results in complete cleft palate in mice. Multi-omics analyses (RNA-seq and CUT&Tag-seq) reveal that Ash2l loss causes genome-wide reduction of H3K4me3 enrichment at key developmental genes, most notably Wnt5b, leading to their transcriptional downregulation. Functionally, Ash2l deficiency impairs proliferation and osteogenic differentiation of palatal mesenchymal cells, resulting in stunted palatal shelf growth and disrupted osteogenesis. Pharmacological activation of WNT signaling downstream of Wnt5b partially rescues these cellular defects, confirming the functional relevance of this axis.Conclusion  These findings establish ASH2L-mediated H3K4me3 as a critical epigenetic regulator of palatal development through WNT5B modulation, and identify potential therapeutic targets for cleft palate.
SN  - 1756-8935
ER  -