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Integrated multi-omics reveal polycomb repressive complex 2 restricts human trophoblast induction.

Published version
Peer-reviewed

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Article

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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.

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Funder: The Marks lab is supported by an NWO-XS grant


Funder: M.V. is part of the Oncode Institute, which is partly funded by the Dutch Cancer Society


Funder: D.W.Z. is part of the Oncode Institute, which is partly funded by the Dutch Cancer Society

Keywords

Cell Differentiation, Chromatin, Histones, Humans, Pluripotent Stem Cells, Polycomb Repressive Complex 2, Trophoblasts

Journal Title

Nat Cell Biol

Conference Name

Journal ISSN

1465-7392
1476-4679

Volume Title

24

Publisher

Springer Science and Business Media LLC
Sponsorship
Wellcome Trust (102160/B/13/Z)
Wellcome Trust (215116/Z/18/Z)