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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 naive pluripotent stem cell chromatin, 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, while 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.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Early Embryonic Cell, Embryonic Stem Cell

SUBMITTER: Natarajan Bhanu

LAB HEAD: Benjamin A Garcia

PROVIDER: PXD032792 | Pride | 2022-05-09

REPOSITORIES: Pride

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Integrated Multi-Omics Reveal Polycomb Repressive Complex 2 Restricts Human Trophoblast Induction

Project description: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 apply multi-omics to comprehensively define the chromatin-associated proteome, histone post-translational modifications and transcriptome of human naive and primed pluripotent stem cells. Integrating the chromatin-bound proteome and histone modification data sets reveals differences in the relative abundance and activities of distinct chromatin modules, identifying a strong enrichment of Polycomb Repressive Complex 2 (PRC2)-associated H3K27me3 in naive pluripotent stem cell chromatin. Single-cell approaches and human blastoid models reveal that PRC2 activity acts as a chromatin barrier restricting the differentiation of naive cells towards the trophoblast lineage, and inhibiting PRC2 promotes trophoblast fate induction and cavity formation. 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. Data originating from the LC-MS/MS analysis of the histone PTMs can be consulted via this project.

2022-05-06 | PXD028162 | Pride

Polycomb Repressive Complex 2 Restricts Human Naive Pluripotent Stem Cell to Trophoblast Fate Induction

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An unexpected histone-binding activity for the MIER1 histone deacetylase complex suggests a potential chaperone function.

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Human Naïve Epiblast Cells Possess Unrestricted Lineage Potential

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