Transient suppression of SUMOylation in embryonic stem cells generates embryo-like structures
Jack-Christophe Cossec,
Tatiana Traboulsi,
Sébastien Sart,
Yann Loe-Mie,
Manuel Guthmann,
Ivo A. Hendriks,
Ilan Theurillat,
Michael L. Nielsen,
Maria-Elena Torres-Padilla,
Charles N. Baroud,
Anne Dejean
Affiliations
Jack-Christophe Cossec
Nuclear Organization and Oncogenesis Unit, Department of Cell Biology and Infection, Equipe Labellisée Ligue Nationale Contre le Cancer, Institut Pasteur, Université Paris Cité, 75015 Paris, France; INSERM, U993, 75015 Paris, France; Corresponding author
Tatiana Traboulsi
Nuclear Organization and Oncogenesis Unit, Department of Cell Biology and Infection, Equipe Labellisée Ligue Nationale Contre le Cancer, Institut Pasteur, Université Paris Cité, 75015 Paris, France; INSERM, U993, 75015 Paris, France
Sébastien Sart
LadHyX, CNRS, Ecole Polytechnique, Institut Polytechnique de Paris, 91120 Palaiseau, France; Physical Microfluidics and Bioengineering Unit, Department of Genomes and Genetics, Institut Pasteur, 75015 Paris, France
Yann Loe-Mie
Nuclear Organization and Oncogenesis Unit, Department of Cell Biology and Infection, Equipe Labellisée Ligue Nationale Contre le Cancer, Institut Pasteur, Université Paris Cité, 75015 Paris, France; INSERM, U993, 75015 Paris, France; Institut Pasteur, Université Paris Cité, Bioinformatics and Biostatistics HUB, 75015 Paris, France
Manuel Guthmann
Institute of Epigenetics and Stem Cells, Helmholtz Zentrum München, 81377 München, Germany
Ivo A. Hendriks
Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Ilan Theurillat
Nuclear Organization and Oncogenesis Unit, Department of Cell Biology and Infection, Equipe Labellisée Ligue Nationale Contre le Cancer, Institut Pasteur, Université Paris Cité, 75015 Paris, France; INSERM, U993, 75015 Paris, France; Sorbonne Université, Collège Doctoral, 75005 Paris, France
Michael L. Nielsen
Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Maria-Elena Torres-Padilla
Institute of Epigenetics and Stem Cells, Helmholtz Zentrum München, 81377 München, Germany; Faculty of Biology, Ludwig-Maximilians-Universität, 81377 München, Germany
Charles N. Baroud
LadHyX, CNRS, Ecole Polytechnique, Institut Polytechnique de Paris, 91120 Palaiseau, France; Physical Microfluidics and Bioengineering Unit, Department of Genomes and Genetics, Institut Pasteur, 75015 Paris, France
Anne Dejean
Nuclear Organization and Oncogenesis Unit, Department of Cell Biology and Infection, Equipe Labellisée Ligue Nationale Contre le Cancer, Institut Pasteur, Université Paris Cité, 75015 Paris, France; INSERM, U993, 75015 Paris, France; Corresponding author
Summary: Recent advances in synthetic embryology have opened new avenues for understanding the complex events controlling mammalian peri-implantation development. Here, we show that mouse embryonic stem cells (ESCs) solely exposed to chemical inhibition of SUMOylation generate embryo-like structures comprising anterior neural and trunk-associated regions. HypoSUMOylation-instructed ESCs give rise to spheroids that self-organize into gastrulating structures containing cell types spatially and functionally related to embryonic and extraembryonic compartments. Alternatively, spheroids cultured in a droplet microfluidic device form elongated structures that undergo axial organization reminiscent of natural embryo morphogenesis. Single-cell transcriptomics reveals various cellular lineages, including properly positioned anterior neuronal cell types and paraxial mesoderm segmented into somite-like structures. Transient SUMOylation suppression gradually increases DNA methylation genome wide and repressive mark deposition at Nanog. Interestingly, cell-to-cell variations in SUMOylation levels occur during early embryogenesis. Our approach provides a proof of principle for potentially powerful strategies to explore early embryogenesis by targeting chromatin roadblocks of cell fate change.
