Abstract
Polycomb repressive complex 2 and the epigenetic mark that it deposits, H3K27me3, are evolutionarily conserved and play critical roles in development and cancer. However, their roles in cell fate decisions in early embryonic development remain poorly understood. Here we report that knockout of polycomb repressive complex 2 genes in human embryonic stem cells causes pluripotency loss and spontaneous differentiation toward a meso-endoderm fate, owing to de-repression of BMP signalling. Moreover, human embryonic stem cells with deletion of EZH1 or EZH2 fail to differentiate into ectoderm lineages. We further show that polycomb repressive complex 2-deficient mouse embryonic stem cells also release Bmp4 but retain their pluripotency. However, when converted into a primed state, they undergo spontaneous differentiation similar to that of hESCs. In contrast, polycomb repressive complex 2 is dispensable for pluripotency when human embryonic stem cells are converted into the naive state. Our studies reveal both lineage- and pluripotent state-specific roles of polycomb repressive complex 2 in cell fate decisions.
Highlights
Polycomb repressive complex 2 and the epigenetic mark that it deposits, H3K27me[3], are evolutionarily conserved and play critical roles in development and cancer
PRC2 is required for pluripotency in human ESCs (hESCs)
We included multiple hESC lines in our analysis to rule out the possible variations between cell lines (Fig. 1b). Guide RNAs (gRNAs)/Cas[9] and the designed targeting vector were electroporated into H1 or H9 hESCs, and the positive clones were subsequently selected by neomycin or puromycin under defined culture conditions (Fig. 1b)
Summary
Polycomb repressive complex 2 and the epigenetic mark that it deposits, H3K27me[3], are evolutionarily conserved and play critical roles in development and cancer Their roles in cell fate decisions in early embryonic development remain poorly understood. We report that knockout of polycomb repressive complex 2 genes in human embryonic stem cells causes pluripotency loss and spontaneous differentiation toward a meso-endoderm fate, owing to de-repression of BMP signalling. When converted into a primed state, they undergo spontaneous differentiation similar to that of hESCs. In contrast, polycomb repressive complex 2 is dispensable for pluripotency when human embryonic stem cells are converted into the naive state. Whole-genome studies have revealed that PRC2 and its mark H3K27me[3] occupy critical developmental genes in both human and mouse embryonic stem cells (ESCs)[2, 3]. We found that PRC2 is required for maintaining pluripotency in only the primed state but not in the naive state
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