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OVOL2 Reinforces Epithelial Identity and Mediates Syncytiotrophoblast Formation in the Mouse Placenta [ChIP-Seq]

ABSTRACT: The placenta establishes the interface between maternal and fetal tissues during pregnancy, enabling the selective exchange of nutrients and gases between maternal and fetal circulations. In humans and mice, this exchange surface is lined by a multinucleated epithelial layer called the syncytiotrophoblast (SynT). SynT formation from trophoblast precursors requires epithelial plasticity to permit cell differentiation, fusion, and morphogenesis, while preserving epithelial integrity to maintain the maternal-fetal exchange barrier. However, the mechanisms that safeguard epithelial features during SynT development remain unclear. OVO-like 2 (OVOL2), a transcriptional repressor of mesenchymal programs and key regulator of epithelial identity, is highly expressed in the mouse placenta and essential for its development. We hypothesized that OVOL2 promotes SynT lineage formation by restricting mesenchymal transformation during trophoblast differentiation. To test this, placental development was examined following Ovol2+/- matings, and wild-type and Ovol2-deficient trophoblast stem cells were analyzed under stem conditions or differentiated with CHIR99021 to enrich for SynT lineages. SynT lineage development was disrupted in both Ovol2-deficient placentas and differentiating trophoblast stem cells. Chromatin profiling identified OVOL2 binding near genes associated with epithelial-to-mesenchymal transition, including Id1, Zeb1, and Vim, which were upregulated in Ovol2-deficient trophoblasts. Consistent with these observations, Ovol2-deficient cells showed elevated levels of mesenchymal markers such as ZEB1 and Vimentin and reduced levels of epithelial markers including E-cadherin. These findings identify OVOL2 as a critical regulator of SynT lineage formation and epithelial identity in the mouse placenta.

ORGANISM(S): Mus musculus

PROVIDER: GSE324788 | GEO | 2026/08/31

REPOSITORIES: GEO

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Project description:Healthy placental development is essential for reproductive success; failure of the feto-maternal interface results in preeclampsia and intrauterine growth retardation. We found that grainyhead-like 2 (GRHL2), a CP2-type transcription factor, is highly expressed in chorionic trophoblast cells, including basal chorionic trophoblast (BCT) cells located at the chorioallantoic interface in murine placentas. Placentas from Grhl2-deficient mouse embryos displayed defects in BCT cell polarity and basement membrane integrity at the chorioallantoic interface, as well as a severe disruption of labyrinth branchingmorphogenesis.Selective Grhl2 inactivation only in epiblastderived cells rescued all placental defects but phenocopied intraembryonic defects observed in global Grhl2 deficiency, implying the importance of Grhl2 activity in trophectoderm-derived cells. ChIPseq identified 5282 GRHL2 binding sites in placental tissue. By integrating these data with placental gene expression profiles, we identified direct and indirect Grhl2 targets and found a marked enrichment of GRHL2 binding adjacent to genes downregulated in Grhl2−/− placentas, which encoded known regulators of placental development and epithelial morphogenesis. These genes included that encoding the serine protease inhibitor Kunitz type 1 (Spint1), which regulates BCT cell integrity and labyrinth formation. In human placenta, we found that human orthologs of murine GRHL2 and its targets displayed co-regulation and were expressed in trophoblast cells in a similar domain as in mouse placenta. Our data indicate that a conserved Grhl2-coordinated gene network controls trophoblast branching morphogenesis, thereby facilitating development of the site of feto-maternal exchange. This might have implications for syndromes related to placental dysfunction. In vivo genome-wide examination of binding sites of the transcription factor GRHL2 by ChIP-seq using wild-type murine E17.5 placenta tissue. Two samples in total: one GRHL2 ChIP sample and one IgG ChIP sample using wild-type placentas tissue as antibody control.

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OVOL2 Reinforces Epithelial Identity and Mediates Syncytiotrophoblast Formation in the Mouse Placenta [ChIP-Seq]

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