biostudies-literatureLi MAnhui Science and Technology Department (Department of Science and Technology of Anhui Province)National Natural Science Foundation of China (National Science Foundation of China)1100https://www.ebi.ac.uk/biostudies/studies/S-EPMC11380689biostudies-literatureUnknown7(1)PHD2 is essential in modulating HIF-1α levels upon oxygen fluctuations. Hypoxia, a hallmark of uterus, and HIF-1α have recently emerged as opposing regulators of mesendoderm specification, suggesting a role for PHD2 therein. We found that PHD2 expression initially covered the epiblast and gradually receded from the primitive streak, which was identical to hypoxia and exclusive to HIF-1α. The investigations performed in mESCs, embryoids, and mouse embryos together demonstrated that PHD2 negatively regulated mesendoderm specification. Single-cell RNA sequencing revealed that PHD2 governed the transition from epiblast to mesendoderm. The downstream effect of PHD2 relied on the HIF-1α regulated Wnt/β-catenin pathway, while it was regulated upstream by miR-429. In summary, our research highlighCommunications biologyPHD2 safeguards modest mesendoderm development.PMC113806892208085MH209, 1808085QH23431701289Liu YJin HLong HZhu GShen XLi MZhao YfalsePHD2 safeguards modest mesendoderm development.PHD2 is essential in modulating HIF-1α levels upon oxygen fluctuations. Hypoxia, a hallmark of uterus, and HIF-1α have recently emerged as opposing regulators of mesendoderm specification, suggesting a role for PHD2 therein. We found that PHD2 expression initially covered the epiblast and gradually receded from the primitive streak, which was identical to hypoxia and exclusive to HIF-1α. The investigations performed in mESCs, embryoids, and mouse embryos together demonstrated that PHD2 negatively regulated mesendoderm specification. Single-cell RNA sequencing revealed that PHD2 governed the transition from epiblast to mesendoderm. The downstream effect of PHD2 relied on the HIF-1α regulated Wnt/β-catenin pathway, while it was regulated upstream by miR-429. In summary, our research highligh2024-01-01T00:00:00Z2024 Sep2026-05-28T01:42:11.174Z2025-04-21T17:02:52.589ZS-EPMC113806893924463610.1038/s42003-024-06824-z