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整合多组学揭示 Polycomb 抑制复合物 2 限制人滋养层诱导。

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

机构信息

Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences (RIMLS), Oncode Institute, Radboud University Nijmegen, Nijmegen, The Netherlands.

Department of Development and Regeneration, Leuven Stem Cell Institute, Leuven Institute for Single Cell Omics (LISCO), KU Leuven, Leuven, Belgium.

出版信息

Nat Cell Biol. 2022 Jun;24(6):858-871. doi: 10.1038/s41556-022-00932-w. Epub 2022 Jun 13.

DOI:10.1038/s41556-022-00932-w
PMID:35697783
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9203278/
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.

摘要

人类原始多能干细胞具有无限制的谱系潜能。在这种特性的支持下，原始细胞被认为缺乏基于染色质的谱系障碍。然而，这一假设尚未得到验证。在这里，我们定义了人类原始和初始多能干细胞的染色质相关蛋白质组、组蛋白翻译后修饰和转录组。我们的综合分析揭示了不同染色质模块的相对丰度和活性的差异。我们发现，在原始多能干细胞的染色质中，多梳抑制复合物 2（PRC2）相关的 H3K27me3 强烈富集，并且在决定谱系的基因（包括滋养层调节剂）的启动子处富集 H3K27me3。PRC2 活性作为一种染色质障碍，限制了原始细胞向滋养层谱系的分化，而 PRC2 的抑制则促进了人类胚泡中滋养层命运的诱导和腔的形成。总之，我们的结果表明，人类原始多能干细胞不是表观遗传上无限制的，而是具有相反的诱导替代细胞命运的染色质机制。

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