Transient suppression of SUMOylation in embryonic stem cells generates embryo-like structures

Jack-Christophe Cossec (1) , Tatiana Traboulsi (1) , Sébastien Sart (2, 3) , Yann Loe-Mie (1, 4) , Manuel Guthmann (5) , Ivo Hendriks (6) , Ilan Theurillat (1, 7) , Michael Nielsen (6) , Maria-Elena Torres-Padilla (5, 8) , Charles N. Baroud (2, 3) , Anne Dejean (1)

1 Organisation Nucléaire et Oncogenèse / Nuclear Organization and Oncogenesis
2 LadHyX - Laboratoire d'hydrodynamique
3 Microfluidique Physique et Bio-ingénierie - Physical Microfluidics and Bioengineering
4 Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB
5 Helmholtz Zentrum München = German Research Center for Environmental Health
6 UCPH - University of Copenhagen = Københavns Universitet
7 Collège Doctoral
8 LMU - Ludwig-Maximilians-Universität München

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.

Keywords: synthetic embryos; SUMOylation; embryonic stem cells; cell identity; epigenetics; microfluidics; gastruloids; embryoids; chromatin

Domains: Cellular Biology

Jack-Christophe Cossec, Tatiana Traboulsi, Sébastien Sart, Yann Loe-Mie, Manuel Guthmann, et al.. Transient suppression of SUMOylation in embryonic stem cells generates embryo-like structures. Cell Reports, 2023, 42 (4), pp.112380. ⟨10.1016/j.celrep.2023.112380⟩. ⟨pasteur-04081183⟩