PT  - JOURNAL ARTICLE
AU  - Maud de Dieuleveult
AU  - Marjorie Leduc
AU  - Eralda Salataj
AU  - Céline Ransy
AU  - Julien Dairou
AU  - Kengo Homma
AU  - Morgane Le Gall
AU  - Pascale Bossard
AU  - Anne Lombès
AU  - Frédéric Bouillaud
AU  - Laure Ferry
AU  - Pierre-Antoine Defossez
AU  - Jean-Charles Cadoret
AU  - Hidenori Ichijo
AU  - Stephen A. Wood
AU  - François Guillonneau
AU  - Ralf Dressel
AU  - Benoit Miotto
TI  - USP9X deubiquitinase couples the pluripotency network and cell metabolism to regulate ESC differentiation potential
AID  - 10.1101/2020.01.13.904904
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.01.13.904904
4099  - http://biorxiv.org/content/early/2020/01/14/2020.01.13.904904.short
4100  - http://biorxiv.org/content/early/2020/01/14/2020.01.13.904904.full
AB  - Embryonic stem cells (ESC) have the unique ability to differentiate into all three germ cell layers. ESC transition through different states of pluripotency in response to growth factor signals and environmental cues before becoming terminally differentiated. Here, we demonstrated, by a multi-omic strategy, that the deubiquitinase USP9X regulates the developmental potential of ESC, and their transition from a naive to a more developmentally advance, or primed, state of pluripotency. We show that USP9X facilitates developmental gene expression and induces modifications of the mitochondrial bioenergetics, including decreased routing of pyruvate towards its oxidation and reduced respiration. In addition, USP9X binds to the pluripotency factor ESRRB, regulates its abundance and the transcriptional levels of a subset of its target genes. Finally, under permissive culture conditions, depletion of Usp9X accelerates cell differentiation in all cell lineages. We thus identified a new regulator of naive pluripotency and show that USP9X couples ESRRB pluripotency transcriptional network and cellular metabolism, both of which are important for ESC fate and pluripotency.