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Cossec, J.C.* ; Traboulsi, T.* ; Sart, S.* ; Loe-Mie, Y.* ; Guthmann, M. ; Hendriks, I.A.* ; Theurillat, I.* ; Nielsen, M.L.* ; Torres-Padilla, M.E. ; Baroud, C.N.* ; Dejean, A.*

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

Cell Rep. 42:112380 (2023)

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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.

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