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Stem Cell Reports. 2018 Apr 10;10(4):1355-1368. doi: 10.1016/j.stemcr.2018.02.014. Epub 2018 Mar 22.

A Critical Role of TET1/2 Proteins in Cell-Cycle Progression of Trophoblast Stem Cells.

Author information

1
Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK; Centre for Trophoblast Research, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
2
Imaging Facility, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
3
Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
4
Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK; Centre for Trophoblast Research, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK. Electronic address: myriam.hemberger@babraham.ac.uk.

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 the epithelial integrity of TSCs. For the more abundantly expressed TET1, we show that this is achieved by binding to critical epithelial genes, notably E-cadherin, which becomes hyper-methylated and downregulated in the absence of TET1. The epithelial-to-mesenchymal transition phenotype of mutant TSCs is accompanied by centrosome duplication and separation defects. Moreover, we identify a role of TET1 in maintaining cyclin B1 stability, thereby acting as 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.

KEYWORDS:

TET proteins; cell cycle; differentiation; endoreduplication; mitosis; self-renewal; trophoblast giant cells; trophoblast stem cells

PMID:
29576538
PMCID:
PMC5998911
DOI:
10.1016/j.stemcr.2018.02.014
[Indexed for MEDLINE]
Free PMC Article

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