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Title

Novel Functions of Geminin as a Regulator of Mesodermal and Endodermal Fate Acquisition

Date of Award

Winter 12-15-2013

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Developmental, Regenerative, & Stem Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Embryonic cells utilize 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 over-expressed 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 maintains Polycomb repressor complex occupancy at mesendodermal loci and decreases trimethylation of histone H3 lysine 4, which is a histone modification associated 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.

Language

English (en)

Chair and Committee

Kristen L. Kroll

Committee Members

Shiming Chen, Kyunghee Choi, Fanxin Long, Jason C. Mills, Lilianna Solnica-Krezel

Comments

Permanent URL: https://doi.org/10.7936/K76D5QXX

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