KAT8-mediated H4K16ac is essential for sustaining trophoblast self-renewal and proliferation via regulating CDX2.
Shilei BiLijun HuangYongjie ChenZhenhua HuShanze LiYifan WangBaoying HuangLizi ZhangYuanyuan HuangBeibei DaiLili DuZhaowei TuYijing WangDan XuXiaotong XuWen SunJulia KzhyshkowskaHaibin WangDunjin ChenFengchao WangShuang ZhangPublished in: Nature communications (2024)
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.
Keyphrases
- stem cells
- rna seq
- single cell
- gene expression
- end stage renal disease
- newly diagnosed
- ejection fraction
- poor prognosis
- preterm infants
- oxidative stress
- epithelial mesenchymal transition
- signaling pathway
- dna methylation
- pregnancy outcomes
- mesenchymal stem cells
- ischemia reperfusion injury
- long non coding rna
- smoking cessation
- weight loss
- gestational age
- heat shock protein