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  Destabilization of pluripotency in the absence of Mad2l2.

Pirouz, M., Rahjouei, A., Shamsi, F., Eckermann, K. N., Salinas-Riester, G., Pommerenke, C., et al. (2015). Destabilization of pluripotency in the absence of Mad2l2. Cell Cycle, 14(10), 1596-1610. doi:10.1080/15384101.2015.1026485.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0026-B7D7-F Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-6D2B-B
Genre: Journal Article

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 Creators:
Pirouz, M.1, Author              
Rahjouei, A.1, Author              
Shamsi, F., Author
Eckermann, K. N., Author
Salinas-Riester, G., Author
Pommerenke, C., Author
Kessel, M.1, Author              
Affiliations:
1Research Group of Developmental Biology, MPI for Biophysical Chemistry, Max Planck Society, ou_578586              

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Free keywords: Embryonic stem cells, pluripotency, differentiation, primitive endoderm, MAP kinase, Mad2B, Rev7
 Abstract: The induction and maintenance of pluripotency requires the expression of several core factors at appropriate levels (Oct4, Sox2, Klf4, Prdm14). A subset of these proteins (Oct4, Sox2, Prdm14) also plays crucial roles for the establishment of primordial germ cells (PGCs). Here we demonstrate that the Mad2l2 (MAD2B, Rev7) gene product is not only required by PGCs, but also by pluripotent embryonic stem cells (ESCs), depending on the growth conditions. Mad2l2−/− ESCs were unstable in LIF/serum medium, and differentiated into primitive endoderm. However, they could be stably propagated using small molecule inhibitors of MAPK signaling. Several components of the MAPK cascade were up- or downregulated even in undifferentiated Mad2l2−/− ESCs. Global levels of repressive histone H3 variants were increased in mutant ESCs, and the epigenetic signatures on pluripotency-, primitive endoderm-, and MAPK-related loci differed. Thus, H3K9me2 repressed the Nanog promoter, while the promoter of Gata4 lost H3K27me3 and became de-repressed in LIF/serum condition. Promoters associated with genes involved in MAPK signaling also showed misregulation of these histone marks. Such epigenetic modifications could be indirect consequences of mutating Mad2l2. However, our previous observations suggested the histone methyltransferases as direct (G9a) or indirect (Ezh2) targets of Mad2l2. In effect, the intricate balance necessary for pluripotency becomes perturbed in the absence of Mad2l2.

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Language(s): eng - English
 Dates: 20152015-05-19
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1080/15384101.2015.1026485
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Title: Cell Cycle
Source Genre: Journal
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Pages: - Volume / Issue: 14 (10) Sequence Number: - Start / End Page: 1596 - 1610 Identifier: -