Beta-catenin Associated Protein Complex Maintains Ground State Mouse Embryonic Stem Cell by Regulating Germline Development

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Issue Date
2016-12-31Author
Tao, Fang
Publisher
University of Kansas
Format
98 pages
Type
Dissertation
Degree Level
Ph.D.
Discipline
Pathology & Laboratory Medicine
Rights
Copyright held by the author.
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Show full item recordAbstract
Mouse embryonic stem (ES) cells cultured in defined medium with MEK and GSK3 inhibitors(2i) resemble the pre-implantation epiblast in the ground state, with full development capacity including the somatic lineages and the germline. Although beta- catenin is known to be crucial for naive pluripotency of ES cells, the mechanism is not fully understood. Here I show that beta-catenin interacts with a repressive protein complex to maintain the ground state of ES cells by fine-tuning the germline development potential of ES cells. I use the mouse ES cell to show that absence of beta-catenin impairs ES cell self-renewal without affecting the core self-renewal circuitry of Oct4, Sox2 and Nanog as well as other pluripotency factors. However, beta-catenin-deficient cells show a primed state transcriptional signature with perturbed gene expression of germline and neuronal lineage. Knockdown of Tcf7l1, the repressor in canonical Wnt signaling pathway, does not completely rescue the beta-catenin-deficient phenotype of ES cells. Mechanistically, beta-catenin forms a novel biochemical complex with E2F6, HP1gamma and HMGA2 to restrain ES cells from differentiation by co-occupying the promoter of germline and neuronal lineage regulators independent of TCF7L1. Moreover, beta-catenin functions differentially in early and late germ cell development, and keeps balance with E2F6 to prevent premature meiosis initiation in ES cells. Overall, my study shows that beta-catenin forms a repressive protein complex with E2F6, HP1gamma and HMGA2 to maintain ground state by orchestrating the development plasticity of ES cells.
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