Integrated multi-omics reveal polycomb repressive complex 2 restricts human trophoblast induction
- PMID: 35697783
- PMCID: PMC9203278
- DOI: 10.1038/s41556-022-00932-w
Integrated multi-omics reveal polycomb repressive complex 2 restricts human trophoblast induction
Abstract
Human naive pluripotent stem cells have unrestricted lineage potential. Underpinning this property, naive cells are thought to lack chromatin-based lineage barriers. However, this assumption has not been tested. Here we define the chromatin-associated proteome, histone post-translational modifications and transcriptome of human naive and primed pluripotent stem cells. Our integrated analysis reveals differences in the relative abundance and activities of distinct chromatin modules. We identify a strong enrichment of polycomb repressive complex 2 (PRC2)-associated H3K27me3 in the chromatin of naive pluripotent stem cells and H3K27me3 enrichment at promoters of lineage-determining genes, including trophoblast regulators. PRC2 activity acts as a chromatin barrier restricting the differentiation of naive cells towards the trophoblast lineage, whereas inhibition of PRC2 promotes trophoblast-fate induction and cavity formation in human blastoids. Together, our results establish that human naive pluripotent stem cells are not epigenetically unrestricted, but instead possess chromatin mechanisms that oppose the induction of alternative cell fates.
© 2022. The Author(s).
Conflict of interest statement
The Institute for Molecular Biotechnology, Austrian Academy of Sciences has filed patent application no. EP21151455.9 describing the protocols for human blastoid formation and for the blastoid–endometrium interaction assay. A.J. and N.R. are the inventors on this patent. All other authors declare no competing interests.
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Comment in
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PRC2 shields the potency of human stem cells.Nat Cell Biol. 2022 Jun;24(6):806-808. doi: 10.1038/s41556-022-00937-5. Nat Cell Biol. 2022. PMID: 35697784 No abstract available.
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