Geminin restrains mesendodermal fate acquisition of embryonic stem cells and is associated with antagonism of Wnt signaling and enhanced polycomb-mediated repression

Elizabeth A. Caronna, Ethan S. Patterson, Pamela M. Hummert, Kristen L. Kroll

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Embryonic cells use both growth factor signaling and cell intrinsic transcriptional and epigenetic regulation to acquire early cell fates. Underlying mechanisms that integrate these cues are poorly understood. Here, we investigated the role of Geminin, a nucleoprotein that interacts with both transcription factors and epigenetic regulatory complexes, during fate acquisition of mouse embryonic stem cells. In order to determine Geminin's role in mesendoderm formation, a process which occurs during embryonic gastrulation, we selectively overexpressed or knocked down Geminin in an in vitro model of differentiating mouse embryonic stem cells. We found that Geminin antagonizes mesendodermal fate acquisition, while these cells instead maintain elevated expression of genes associated with pluripotency of embryonic stem cells. During mesendodermal fate acquisition, Geminin knockdown promotes Wnt signaling, while Bmp, Fgf, and Nodal signaling are not affected. Moreover, we showed that Geminin facilitates the repression of mesendodermal genes that are regulated by the Polycomb repressor complex. Geminin directly binds several of these genes, while Geminin knockdown in mesendodermal cells reduces Polycomb repressor complex occupancy at these loci and increases trimethylation of histone H3 lysine 4, which correlates with active gene expression. Together, these results indicate that Geminin is required to restrain mesendodermal fate acquisition of early embryonic cells and that this is associated with both decreased Wnt signaling and enhanced Polycomb repressor complex retention at mesendodermal genes.

Original languageEnglish
Pages (from-to)1477-1487
Number of pages11
JournalSTEM CELLS
Volume31
Issue number8
DOIs
StatePublished - Aug 2013

Keywords

  • Embryonic stem cell
  • Geminin
  • Mesendoderm
  • Polycomb complex
  • Wnt

Fingerprint

Dive into the research topics of 'Geminin restrains mesendodermal fate acquisition of embryonic stem cells and is associated with antagonism of Wnt signaling and enhanced polycomb-mediated repression'. Together they form a unique fingerprint.

Cite this