Esrrb guides naive pluripotent cells through the formative transcriptional programme

Elena Carbognin; Valentina Carlini; Francesco Panariello; Martina Chieregato; Elena Guerzoni; Davide Benvegnù; Valentina Perrera; Cristina Malucelli; Marcella Cesana; Antonio Grimaldi; Margherita Mutarelli; Annamaria Carissimo; Eitan Tannenbaum; Hillel Kugler; Jamie A. Hackett; Davide Cacchiarelli; Graziano Martello

doi:10.1038/s41556-023-01131-x

Esrrb guides naive pluripotent cells through the formative transcriptional programme

Elena Carbognin, Valentina Carlini, Francesco Panariello, Martina Chieregato, Elena Guerzoni, Davide Benvegnù, Valentina Perrera, Cristina Malucelli, Marcella Cesana, Antonio Grimaldi, Margherita Mutarelli, Annamaria Carissimo, Eitan Tannenbaum, Hillel Kugler, Jamie A. Hackett, Davide Cacchiarelli, Graziano Martello

Bar-Ilan University - The Alexander Kofkin Faculty of Engineering

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

During embryonic development, naive pluripotent epiblast cells transit to a formative state. The formative epiblast cells form a polarized epithelium, exhibit distinct transcriptional and epigenetic profiles and acquire competence to differentiate into all somatic and germline lineages. However, we have limited understanding of how the transition to a formative state is molecularly controlled. Here we used murine embryonic stem cell models to show that ESRRB is both required and sufficient to activate formative genes. Genetic inactivation of Esrrb leads to illegitimate expression of mesendoderm and extra-embryonic markers, impaired formative expression and failure to self-organize in 3D. Functionally, this results in impaired ability to generate formative stem cells and primordial germ cells in the absence of Esrrb. Computational modelling and genomic analyses revealed that ESRRB occupies key formative genes in naive cells and throughout the formative state. In so doing, ESRRB kickstarts the formative transition, leading to timely and unbiased capacity for multi-lineage differentiation.

Original language	English
Pages (from-to)	643-657
Number of pages	15
Journal	Nature Cell Biology
Volume	25
Issue number	5
Early online date	27 Apr 2023
DOIs	https://doi.org/10.1038/s41556-023-01131-x
State	Published - May 2023

Bibliographical note

Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.

Funding

We thank A. Smith for critical reading of the manuscript. This work was supported by Fondazione Telethon Core Grant, Armenise-Harvard Foundation Career Development Award, European Research Council (grant agreement 759154, CellKarma) and the Rita-Levi Montalcini programme from Ministero dell'istruzione, dell'università e della ricerca (MIUR) to D.C. and M.C. We thank TIGEM NGS core, NEGEDIA and A. Manfredi for genomic library preparation and sequencing run. Work in J.A.H.’s laboratory is supported by programme grants from the European Molecular Biology Laboratory (EMBL). Work in H.K.’s group is supported by the ISRAEL SCIENCE FOUNDATION (grant no. 190/19). G.M.’s laboratory is supported by grants from the Giovanni Armenise–Harvard Foundation, the Telethon Foundation (GJC21157), Microsoft Research and an ERC Starting Grant (MetEpiStem).

Funders	Funder number
Microsoft Research
Giovanni Armenise-Harvard Foundation
European Molecular Biology Laboratory
European Commission	759154
Fondazione Telethon	GJC21157
Ministero dell’Istruzione, dell’Università e della Ricerca
Israel Science Foundation	190/19

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Carbognin, E., Carlini, V., Panariello, F., Chieregato, M., Guerzoni, E., Benvegnù, D., Perrera, V., Malucelli, C., Cesana, M., Grimaldi, A., Mutarelli, M., Carissimo, A., Tannenbaum, E., Kugler, H., Hackett, J. A., Cacchiarelli, D., & Martello, G. (2023). Esrrb guides naive pluripotent cells through the formative transcriptional programme. Nature Cell Biology, 25(5), 643-657. https://doi.org/10.1038/s41556-023-01131-x

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abstract = "During embryonic development, naive pluripotent epiblast cells transit to a formative state. The formative epiblast cells form a polarized epithelium, exhibit distinct transcriptional and epigenetic profiles and acquire competence to differentiate into all somatic and germline lineages. However, we have limited understanding of how the transition to a formative state is molecularly controlled. Here we used murine embryonic stem cell models to show that ESRRB is both required and sufficient to activate formative genes. Genetic inactivation of Esrrb leads to illegitimate expression of mesendoderm and extra-embryonic markers, impaired formative expression and failure to self-organize in 3D. Functionally, this results in impaired ability to generate formative stem cells and primordial germ cells in the absence of Esrrb. Computational modelling and genomic analyses revealed that ESRRB occupies key formative genes in naive cells and throughout the formative state. In so doing, ESRRB kickstarts the formative transition, leading to timely and unbiased capacity for multi-lineage differentiation.",

author = "Elena Carbognin and Valentina Carlini and Francesco Panariello and Martina Chieregato and Elena Guerzoni and Davide Benvegn{\`u} and Valentina Perrera and Cristina Malucelli and Marcella Cesana and Antonio Grimaldi and Margherita Mutarelli and Annamaria Carissimo and Eitan Tannenbaum and Hillel Kugler and Hackett, {Jamie A.} and Davide Cacchiarelli and Graziano Martello",

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Carbognin, E, Carlini, V, Panariello, F, Chieregato, M, Guerzoni, E, Benvegnù, D, Perrera, V, Malucelli, C, Cesana, M, Grimaldi, A, Mutarelli, M, Carissimo, A, Tannenbaum, E, Kugler, H, Hackett, JA, Cacchiarelli, D & Martello, G 2023, 'Esrrb guides naive pluripotent cells through the formative transcriptional programme', Nature Cell Biology, vol. 25, no. 5, pp. 643-657. https://doi.org/10.1038/s41556-023-01131-x

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AU - Carbognin, Elena

AU - Carlini, Valentina

AU - Panariello, Francesco

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AU - Benvegnù, Davide

AU - Perrera, Valentina

AU - Malucelli, Cristina

AU - Cesana, Marcella

AU - Grimaldi, Antonio

AU - Mutarelli, Margherita

AU - Carissimo, Annamaria

AU - Tannenbaum, Eitan

AU - Kugler, Hillel

AU - Hackett, Jamie A.

AU - Cacchiarelli, Davide

AU - Martello, Graziano

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Esrrb guides naive pluripotent cells through the formative transcriptional programme

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