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β-catenin associated protein complex maintains ground state mouse embryonic stem cell by regulating lineage 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 β-catenin is known to be crucial for naive pluripotency of ES cells, the mechanism is not fully understood. Here we showed that β-catenin interacted with a repressive protein complex to maintain the ground state of ES cells by fine-tuning their lineage development potential. Absence of β-catenin impaired ES cell self-renewal without affecting the core self-renewal circuitry of Oct4, Sox2 and Nanog as well as other pluripotency factors. However, β-catenin-deficient cells showed a primed state transcriptional signature with perturbed expression of germline and neuronal lineage genes. Knockdown of Tcf7l1, the repressor in canonical Wnt signaling pathway, did not completely rescue the β-catenin-deficient phenotype of ES cells. Mechanistically, β-catenin formed a novel biochemical complex with E2F6, HP1γ and HMGA2 to restrain ES cells from differentiation by co-occupying the promoters of germline and neuronal lineage regulators independent of TCF7L1. Overall, out work showed that β-catenin maintained ground state ES cells by orchestrating their development plasticity through a repressive protein complex with E2F6, HP1γ and HMGA2.

ORGANISM(S): Mus musculus

PROVIDER: GSE108620 | GEO | 2020/08/20

REPOSITORIES: GEO

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ChIP-seq experiment of mouse embryonic stem cells (mESCs), assessing beta-catenin DNA binding in wild type mESCs and TCF/LEF quadruple knock-out mESCs.

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