KAT8-mediated H4K16ac is essential for sustaining trophoblast self-renewal and proliferation via regulating CDX2

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 () and Shuang Zhang ()
Additional contact information
Shilei Bi: The Third Affiliated Hospital of Guangzhou Medical University
Lijun Huang: The Third Affiliated Hospital of Guangzhou Medical University
Yongjie Chen: Capital Medical University. Beijing Maternal and Child Health Care Hospital
Zhenhua Hu: The Third Affiliated Hospital of Guangzhou Medical University
Shanze Li: National Institute of Biological Sciences
Yifan Wang: The Third Affiliated Hospital of Guangzhou Medical University
Baoying Huang: The Third Affiliated Hospital of Guangzhou Medical University
Lizi Zhang: The Third Affiliated Hospital of Guangzhou Medical University
Yuanyuan Huang: The Third Affiliated Hospital of Guangzhou Medical University
Beibei Dai: The Third Affiliated Hospital of Guangzhou Medical University
Lili Du: The Third Affiliated Hospital of Guangzhou Medical University
Zhaowei Tu: The Third Affiliated Hospital of Guangzhou Medical University
Yijing Wang: National Institute of Biological Sciences
Dan Xu: National Institute of Biological Sciences
Xiaotong Xu: National Institute of Biological Sciences
Wen Sun: The Third Affiliated Hospital of Guangzhou Medical University
Julia Kzhyshkowska: Mannheim Institute of Innate Immunosciences (MI3), Medical Faculty Mannheim, Heidelberg University
Haibin Wang: The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University
Dunjin Chen: The Third Affiliated Hospital of Guangzhou Medical University
Fengchao Wang: National Institute of Biological Sciences
Shuang Zhang: The Third Affiliated Hospital of Guangzhou Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-49930-6

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