Destabilization of pluripotency in the absence of Mad2l2

Mehdi Pirouz, Ali Rahjouei, Farnaz Shamsi, Kolja Neil Eckermann, Gabriela Salinas-Riester, Claudia Pommerenke, Michael Kessel

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1596-1610
Number of pages15
JournalCell Cycle
Volume14
Issue number10
DOIs
StatePublished - Jan 1 2015

Keywords

  • Differentiation
  • Embryonic stem cells
  • Mad2B
  • MAP kinase
  • Pluripotency
  • Primitive endoderm
  • Rev7

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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