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

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


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 languageEnglish
Pages (from-to)643-657
Number of pages15
JournalNature Cell Biology
Issue number5
Early online date27 Apr 2023
StatePublished - May 2023

Bibliographical note

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


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).

FundersFunder number
Microsoft Research
Giovanni Armenise-Harvard Foundation
European Molecular Biology Laboratory
European Research Council759154
Fondazione TelethonGJC21157
Ministero dell’Istruzione, dell’Università e della Ricerca
Israel Science Foundation190/19


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