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

Abstract

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.