A novel role of Tet1/2 proteins in cell cycle progression of trophoblast stem cells

The ten-eleven translocation (Tet) proteins are well known for their role in maintaining naive pluripotency of embryonic stem cells. Here, we demonstrate that jointly, Tet1 and Tet2 also safeguard the self-renewal potential of trophoblast stem cells (TSCs) and have partially redundant roles in maintaining their epithelial integrity. For the more abundantly expressed Tet1, we demonstrate that this is achieved by binding to critical epithelial genes, notably E-Cadherin, which becomes hyper-methylated and down-regulated in the absence of Tet1. This epithelial-to-mesenchymal transition phenotype is accompanied by centrosome duplication and separation defects. Moreover, we identify a novel role of Tet1 in stabilizing Cyclin B1, thereby acting as a facilitator of mitotic cell cycle progression. As a result, Tet1/2 mutant TSCs are prone to undergo endoreduplicative cell cycles leading to the formation of polyploid trophoblast giant cells. Taken together, our data reveal essential functions of Tet proteins in the trophoblast lineage. ChIP-seq with 1 antibody (anti-Tet1) in one cell type (mouse trophoblast stem cells); RNA-seq of wild-type, Tet1 single knockout and Tet1/2 double knockout trophoblast stem cells, Bisulfite-seq of wild-type and Tet1 single knockout trophoblast stem cells.