Polycomb Repressive Complex 2 Shields Naïve Human Pluripotent Cells from Trophectoderm Differentiation

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2022 May 31

PMID 35637409

Authors

Banushree Kumar

Carmen Navarro

Nerges Winblad

John P Schell

Cheng Zhao

Jere Weltner

Laura Baque-Vidal

Angelo Salazar Mantero

Sophie Petropoulos

Fredrik Lanner

Simon J Elsasser

Affiliations

Soon will be listed here.

Abstract

The first lineage choice in human embryo development separates trophectoderm from the inner cell mass. Naïve human embryonic stem cells are derived from the inner cell mass and offer possibilities to explore how lineage integrity is maintained. Here, we discover that polycomb repressive complex 2 (PRC2) maintains naïve pluripotency and restricts differentiation to trophectoderm and mesoderm lineages. Through quantitative epigenome profiling, we found that a broad gain of histone H3 lysine 27 trimethylation (H3K27me3) is a distinct feature of naïve pluripotency. We define shared and naïve-specific bivalent promoters featuring PRC2-mediated H3K27me3 concomitant with H3K4me3. Naïve bivalency maintains key trophectoderm and mesoderm transcription factors in a transcriptionally poised state. Inhibition of PRC2 forces naïve human embryonic stem cells into an 'activated' state, characterized by co-expression of pluripotency and lineage-specific transcription factors, followed by differentiation into either trophectoderm or mesoderm lineages. In summary, PRC2-mediated repression provides a highly adaptive mechanism to restrict lineage potential during early human development.

Citing Articles

Transient chemical-mediated epigenetic modulation confers unrestricted lineage potential on human primed pluripotent stem cells.

Chen S, He Y, Lv L, Liu B, Li C, Deng H Sci China Life Sci. 2025; .

PMID: 39825205 DOI: 10.1007/s11427-024-2660-3.

Generation of Bona Fide Human Induced Trophoblast Stem Cells by Direct Reprogramming of Term Umbilical Cord Cells.

van Voorden A, Boussata S, Keijser R, Vermij M, Wagner M, Ganzevoort W Int J Mol Sci. 2025; 26(1.

PMID: 39796127 PMC: 11719488. DOI: 10.3390/ijms26010271.

H3K27 dimethylation dynamics reveal stepwise establishment of facultative heterochromatin in early mouse embryos.

Matsuwaka M, Kumon M, Inoue A Nat Cell Biol. 2024; 27(1):28-38.

PMID: 39482357 DOI: 10.1038/s41556-024-01553-1.

Early human development and stem cell-based human embryo models.

Shahbazi M, Pasque V Cell Stem Cell. 2024; 31(10):1398-1418.

PMID: 39366361 PMC: 7617107. DOI: 10.1016/j.stem.2024.09.002.

Multiplexed chromatin immunoprecipitation sequencing for quantitative study of histone modifications and chromatin factors.

Kumar B, Navarro C, Yung P, Lyu J, Salazar Mantero A, Katsori A Nat Protoc. 2024; 20(3):779-809.

PMID: 39363107 DOI: 10.1038/s41596-024-01058-z.

References

Landt S, Marinov G, Kundaje A, Kheradpour P, Pauli F, Batzoglou S . ChIP-seq guidelines and practices of the ENCODE and modENCODE consortia. Genome Res. 2012; 22(9):1813-31. PMC: 3431496. DOI: 10.1101/gr.136184.111. View

Love M, Huber W, Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15(12):550. PMC: 4302049. DOI: 10.1186/s13059-014-0550-8. View

Yan L, Yang M, Guo H, Yang L, Wu J, Li R . Single-cell RNA-Seq profiling of human preimplantation embryos and embryonic stem cells. Nat Struct Mol Biol. 2013; 20(9):1131-9. DOI: 10.1038/nsmb.2660. View

Guo G, von Meyenn F, Rostovskaya M, Clarke J, Dietmann S, Baker D . Epigenetic resetting of human pluripotency. Development. 2017; 144(15):2748-2763. PMC: 5560041. DOI: 10.1242/dev.146811. View

Gafni O, Weinberger L, AlFatah Mansour A, Manor Y, Chomsky E, Ben-Yosef D . Derivation of novel human ground state naive pluripotent stem cells. Nature. 2013; 504(7479):282-6. DOI: 10.1038/nature12745. View

Brons I, Smithers L, Trotter M, Rugg-Gunn P, Sun B, Chuva de Sousa Lopes S . Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature. 2007; 448(7150):191-5. DOI: 10.1038/nature05950. View

Theunissen T, Jaenisch R . Mechanisms of gene regulation in human embryos and pluripotent stem cells. Development. 2017; 144(24):4496-4509. PMC: 5769625. DOI: 10.1242/dev.157404. View

Brunson J . ggalluvial: Layered Grammar for Alluvial Plots. J Open Source Softw. 2023; 5(49). PMC: 10010671. DOI: 10.21105/joss.02017. View

Drukker M, Tang C, Ardehali R, Rinkevich Y, Seita J, Lee A . Isolation of primitive endoderm, mesoderm, vascular endothelial and trophoblast progenitors from human pluripotent stem cells. Nat Biotechnol. 2012; 30(6):531-42. PMC: 3672406. DOI: 10.1038/nbt.2239. View

10.

Galili T, OCallaghan A, Sidi J, Sievert C . heatmaply: an R package for creating interactive cluster heatmaps for online publishing. Bioinformatics. 2017; 34(9):1600-1602. PMC: 5925766. DOI: 10.1093/bioinformatics/btx657. View

11.

Ram O, Goren A, Amit I, Shoresh N, Yosef N, Ernst J . Combinatorial patterning of chromatin regulators uncovered by genome-wide location analysis in human cells. Cell. 2011; 147(7):1628-39. PMC: 3312319. DOI: 10.1016/j.cell.2011.09.057. View

12.

Shakiba N, White C, Lipsitz Y, Yachie-Kinoshita A, Tonge P, Hussein S . CD24 tracks divergent pluripotent states in mouse and human cells. Nat Commun. 2015; 6:7329. PMC: 4490408. DOI: 10.1038/ncomms8329. View

13.

Endoh M, Endo T, Endoh T, Fujimura Y, Ohara O, Toyoda T . Polycomb group proteins Ring1A/B are functionally linked to the core transcriptional regulatory circuitry to maintain ES cell identity. Development. 2008; 135(8):1513-24. DOI: 10.1242/dev.014340. View

14.

Krendl C, Shaposhnikov D, Rishko V, Ori C, Ziegenhain C, Sass S . GATA2/3-TFAP2A/C transcription factor network couples human pluripotent stem cell differentiation to trophectoderm with repression of pluripotency. Proc Natl Acad Sci U S A. 2017; 114(45):E9579-E9588. PMC: 5692555. DOI: 10.1073/pnas.1708341114. View

15.

Tamburri S, Lavarone E, Fernandez-Perez D, Conway E, Zanotti M, Manganaro D . Histone H2AK119 Mono-Ubiquitination Is Essential for Polycomb-Mediated Transcriptional Repression. Mol Cell. 2019; 77(4):840-856.e5. PMC: 7033561. DOI: 10.1016/j.molcel.2019.11.021. View

16.

Ware C, Nelson A, Mecham B, Hesson J, Zhou W, Jonlin E . Derivation of naive human embryonic stem cells. Proc Natl Acad Sci U S A. 2014; 111(12):4484-9. PMC: 3970494. DOI: 10.1073/pnas.1319738111. View

17.

Gel B, Serra E . karyoploteR: an R/Bioconductor package to plot customizable genomes displaying arbitrary data. Bioinformatics. 2017; 33(19):3088-3090. PMC: 5870550. DOI: 10.1093/bioinformatics/btx346. View

18.

Mao Q . BCRP/ABCG2 in the placenta: expression, function and regulation. Pharm Res. 2008; 25(6):1244-55. PMC: 2346511. DOI: 10.1007/s11095-008-9537-z. View

19.

Pan G, Tian S, Nie J, Yang C, Ruotti V, Wei H . Whole-genome analysis of histone H3 lysine 4 and lysine 27 methylation in human embryonic stem cells. Cell Stem Cell. 2008; 1(3):299-312. DOI: 10.1016/j.stem.2007.08.003. View

20.

Nichols J, Smith A . Naive and primed pluripotent states. Cell Stem Cell. 2009; 4(6):487-92. DOI: 10.1016/j.stem.2009.05.015. View