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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE109545 | GEO | 2018/05/02

REPOSITORIES: GEO

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Project description:TET-family enzymes convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. Tet1 and Tet2 are Oct4-regulated enzymes that together sustain 5hmC in mouse embryonic stem (ES) cells. ES cells depleted of Tet1 by RNAi show diminished expression of the Nodal antagonist Lefty1, and display hyperactive Nodal signalling and skewed differentiation into the endoderm-mesoderm lineage in embryoid bodies in vitro. In Fgf4- and heparin-supplemented culture conditions that favor derivation of trophoblast stem (TS) cells, Tet1-depleted ES cells activate the trophoblast stem cell lineage determinant Elf5 and can colonize the placenta in mid-gestation embryo chimeras. Consistent with these findings, Tet1-depleted ES cells form aggressive hemorrhagic teratomas with increased endoderm, reduced neuroectoderm and ectopic appearance of trophoblastic giant cells. Thus Tet1 functions to regulate the lineage differentiation potential of ES cells. Here, we performed whole-genome transcriptome profiling of ES cells stably depleted of Tet1 by shRNA knockdown (Tet1-kd) cultured in either standard ES cell or in TS cell culture conditions. Gene expression changes in Tet1-kd ES cells were fairly modest compared to control (GFP-kd) cells, although gene ontology (GO) analysis of differentially expressed genes yielded many terms related to embryonic development and cell cycle regulation. In TS cell culture conditions, a core set of genes defining trophectodermal cell differentiation, including Cdx2, Eomes and Tead4, was enriched in Tet1-kd compared to GFP-kd cells. A total of 27 samples were analysed with at least 3 replicates in each group. Control/reference samples comprise ES cells cultured in standard ES cell media (true ES cells) and TS cells cultured in Fgf4/heparin-supplemented (TS) media (true TS cells). We compared Tet1-kd ES cells with GFP-kd ES cells cultured in either ES or TS cell media. In addition, we included a set of Tet1-kd subclones (Tet1-kd-sc) cultured in TS cell condition and a set of untransfected ES cells (parental control) cultured in TS cell condition.

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

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