Loss of PRC2 subunits primes lineage choice during exit of pluripotency

Polycomb Repressive Complex 2 (PRC2) is crucial for the coordinated expression of genes during early embryonic development, catalyzing histone H3 lysine 27 trimethylation. Two distinct PRC2 complexes, PRC2.1 and PRC2.2, contain respectively MTF2 and JARID2 in embryonic stem cells (ESCs). In this stu...

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Bibliographic Details
Published in:	Nature communications Vol. 12; no. 1; p. 6985
Main Authors:	Loh, Chet H., van Genesen, Siebe, Perino, Matteo, Bark, Magnus R., Veenstra, Gert Jan C.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 30-11-2021 Nature Publishing Group Nature Portfolio
Subjects:	13/100 38/15 38/39 38/91 631/337/100/2285 631/337/176/2016 64/60 Animals Cell activation Cell Differentiation Derepression Differentiation Embryo cells Embryogenesis Embryoid Bodies Embryonic Development - genetics Embryonic Development - physiology Embryonic growth stage Embryonic Stem Cells Gene expression Gene Silencing Germ Layers Histone H3 Histones Humanities and Social Sciences Lymphocytes, Null Lysine Mice multidisciplinary Null cells Pluripotency Pluripotent Stem Cells - physiology Polycomb group proteins Polycomb Repressive Complex 2 - genetics Polycomb Repressive Complex 2 - metabolism Promoter Regions, Genetic Science Science (multidisciplinary) Stem cell transplantation Stem cells Transcriptional Activation Transcriptome Transcriptomics
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Summary:	Polycomb Repressive Complex 2 (PRC2) is crucial for the coordinated expression of genes during early embryonic development, catalyzing histone H3 lysine 27 trimethylation. Two distinct PRC2 complexes, PRC2.1 and PRC2.2, contain respectively MTF2 and JARID2 in embryonic stem cells (ESCs). In this study, we explored their roles in lineage specification and commitment, using single-cell transcriptomics and mouse embryoid bodies derived from Mtf2 and Jarid2 null ESCs. We observe that the loss of Mtf2 results in enhanced and faster differentiation towards cell fates from all germ layers, while the Jarid2 null cells are predominantly directed towards early differentiating precursors, with reduced efficiency towards mesendodermal lineages. These effects are caused by derepression of developmental regulators that are poised for activation in pluripotent cells and gain H3K4me3 at their promoters in the absence of PRC2 repression. Upon lineage commitment, the differentiation trajectories are relatively similar to those of wild-type cells. Together, our results uncover a major role for MTF2-containing PRC2.1 in balancing poised lineage-specific gene activation, whereas the contribution of JARID2-containing PRC2 is more selective in nature compared to MTF2. These data explain how PRC2 imposes thresholds for lineage choice during the exit of pluripotency. Polycomb Repressive Complex 2, an important regulator of embryonic development, exists in two configurations, PRC2.1 and PRC2.2. Here the authors dissect the functional contributions of these two PRC2 subunits and observed complex-specific alterations in the cell state of pluripotent and early differentiating cells.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-021-27314-4