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

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

  • Nat Cell Biol. 2022 Jun;24(6):858-871. doi: 10.1038/s41556-022-00932-w.
Dick W Zijlmans  # 1,  Irene Talon  # 2,  Sigrid Verhelst  # 3,  Adam Bendall  # 4,  Karlien Van Nerum 2,  Alok Javali 5,  Andrew A Malcolm 4 6,  Sam S F A van Knippenberg 2,  Laura Biggins 7,  San Kit To 2,  Adrian Janiszewski 2,  Danielle Admiraal 8,  Ruth Knops 9,  Nikky Corthout 10,  Bradley P Balaton 2,  Grigorios Georgolopoulos 2,  Amitesh Panda 2,  Natarajan V Bhanu 11,  Amanda J Collier 4,  Charlene Fabian 4,  Ryan N Allsop 2,  Joel Chappell 2,  Thi Xuan Ai Pham 2,  Michael Oberhuemer 2,  Cankat Ertekin 2,  Lotte Vanheer 2,  Paraskevi Athanasouli 2,  Frederic Lluis 2,  Dieter Deforce 3,  Joop H Jansen 9,  Benjamin A Garcia 11,  Michiel Vermeulen 1 8,  Nicolas Rivron 5,  Maarten Dhaenens 12,  Hendrik Marks 13,  Peter J Rugg-Gunn 14 15 16,  Vincent Pasque 17
Affiliations

Affiliations

  • 1 Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences (RIMLS), Oncode Institute, Radboud University Nijmegen, Nijmegen, The Netherlands.
  • 2 Department of Development and Regeneration, Leuven Stem Cell Institute, Leuven Institute for Single Cell Omics (LISCO), KU Leuven, Leuven, Belgium.
  • 3 ProGenTomics, Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium.
  • 4 Epigenetics Programme, Babraham Institute, Cambridge, UK.
  • 5 Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.
  • 6 The Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
  • 7 Bioinformatics Group, Babraham Institute, Cambridge, UK.
  • 8 Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Nijmegen, Nijmegen, The Netherlands.
  • 9 Laboratory of Hematology, Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre (RadboudUMC), Nijmegen, the Netherlands.
  • 10 VIB Center for Brain and Disease Research, KU Leuven, VIB Bioimaging Core, Leuven, Belgium.
  • 11 Epigenetics Institute, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 12 ProGenTomics, Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium. Maarten.Dhaenens@UGent.be.
  • 13 Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Nijmegen, Nijmegen, The Netherlands. Hendrik.Marks@ru.nl.
  • 14 Epigenetics Programme, Babraham Institute, Cambridge, UK. peter.rugg-gunn@babraham.ac.uk.
  • 15 The Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. peter.rugg-gunn@babraham.ac.uk.
  • 16 The Centre for Trophoblast Research, University of Cambridge, Cambridge, UK. peter.rugg-gunn@babraham.ac.uk.
  • 17 Department of Development and Regeneration, Leuven Stem Cell Institute, Leuven Institute for Single Cell Omics (LISCO), KU Leuven, Leuven, Belgium. vincent.pasque@kuleuven.be.
  • # Contributed equally.
PMID: 35697783 DOI: 10.1038/s41556-022-00932-w
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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