KAT8-mediated H4K16ac is essential for sustaining trophoblast self-renewal and proliferation via regulating CDX2
Abnormal trophoblast self-renewal and differentiation during early gestation is the major cause of miscarriage, yet the underlying regulatory mechanisms remain elusive. Here, we show that trophoblast specific deletion of Kat8, a MYST family histone acetyltransferase, leads to extraembryonic ectoderm...
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
03 July 2024
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| In: |
Nature Communications
Year: 2024, Jahrgang: 15, Pages: 1-17 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-024-49930-6 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-024-49930-6 Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-024-49930-6 
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| Verfasserangaben: | Shilei Bi, Lijun Huang, Yongjie Chen, Zhenhua Hu, Shanze Li, Yifan Wang, Baoying Huang, Lizi Zhang, Yuanyuan Huang, Beibei Dai, Lili Du, Zhaowei Tu, Yijing Wang, Dan Xu, Xiaotong Xu, Wen Sun, Julia Kzhyshkowska, Haibin Wang, Dunjin Chen, Fengchao Wang & Shuang Zhang |
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| 245 | 1 | 0 | |a KAT8-mediated H4K16ac is essential for sustaining trophoblast self-renewal and proliferation via regulating CDX2 |c Shilei Bi, Lijun Huang, Yongjie Chen, Zhenhua Hu, Shanze Li, Yifan Wang, Baoying Huang, Lizi Zhang, Yuanyuan Huang, Beibei Dai, Lili Du, Zhaowei Tu, Yijing Wang, Dan Xu, Xiaotong Xu, Wen Sun, Julia Kzhyshkowska, Haibin Wang, Dunjin Chen, Fengchao Wang & Shuang Zhang |
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| 520 | |a Abnormal trophoblast self-renewal and differentiation during early gestation is the major cause of miscarriage, yet the underlying regulatory mechanisms remain elusive. Here, we show that trophoblast specific deletion of Kat8, a MYST family histone acetyltransferase, leads to extraembryonic ectoderm abnormalities and embryonic lethality. Employing RNA-seq and CUT&Tag analyses on trophoblast stem cells (TSCs), we further discover that KAT8 regulates the transcriptional activation of the trophoblast stemness marker, CDX2, via acetylating H4K16. Remarkably, CDX2 overexpression partially rescues the defects arising from Kat8 knockout. Moreover, increasing H4K16ac via using deacetylase SIRT1 inhibitor, EX527, restores CDX2 levels and promoted placental development. Clinical analysis shows reduced KAT8, CDX2 and H4K16ac expression are associated with recurrent pregnancy loss (RPL). Trophoblast organoids derived from these patients exhibit impaired TSC self-renewal and growth, which are significantly ameliorated with EX527 treatment. These findings suggest the therapeutic potential of targeting the KAT8-H4K16ac-CDX2 axis for mitigating RPL, shedding light on early gestational abnormalities. | ||
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