Esrrb guides naive pluripotent cells through the formative transcriptional programme

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

doi:10.1038/s41556-023-01131-x

Cited by 12 publications

(22 citation statements)

References 98 publications

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“…While addition of Rapamycin restored Nanog expression to WT levels in both Pten and Tsc2 KOs, Esrrb and Klf5 expression remained high in Pten KOs. Furthermore, a set of 436 previously identified naïve pluripotency-specific genes (Carbognin et al 2023) consistently showed a significantly stronger reduction in expression levels upon Rapamycin treatment in Tsc2 compared to Pten KOs ( Fig. 1K ).…”

Section: Resultsmentioning

confidence: 83%

“…K, Box plot showing the expression of naïve genes (combination of naïve early and naïve late genes as defined in Carbognin et al 2023) in Pten and Tsc2 KO cells treated with DMSO or Rapamycin as measured by RNA-seq. Data is shown as log2FC relative to WT.…”

Section: Resultsmentioning

confidence: 99%

“…G Heatmap showing ESRRB signal in WT cells in 2iL, N48 and N96 (from Carbognin et al 2023) in a 1.5 kb window around the center of FoxO1 peak categories as defined in A.…”

Section: Resultsmentioning

confidence: 99%

“…Recently it was shown that Esrrb, originally identified as a naïve pluripotency-specific TF, performs additional functions in the initiation of the formative transcription programme (Carbognin et al 2023). To investigate whether FoxO-TFs cooperate with ESRRB, we examined the overlap on chromatin between FOXO1 and ESRRB throughout the pluripotency continuum ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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FoxO transcription factors actuate the formative pluripotency specific gene expression programme

Santini,

Kowald,

Sestini

et al. 2024

Preprint

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Naive pluripotency is sustained by a self-reinforcing gene regulatory network (GRN) comprising core and naive pluripotency-specific transcription factors (TFs). Upon exiting naive pluripotency, ES cells transition through a formative post-implantation-like pluripotent state, where they acquire competence for lineage-choice. However, the mechanisms underlying disengagement from the naive GRN and initiation of the formative GRN are unclear. Here, we demonstrate that phosphorylated AKT acts as a gatekeeper that prevents nuclear localization of FoxO TFs in naive ESCs. PTEN-mediated reduction of AKT activity upon exit from naive pluripotency allows nuclear entry of FoxO TFs, enforcing a cell fate transition by binding and activating formative pluripotency-specific enhancers. Indeed, FoxO TFs are necessary and sufficient for transition from the naive to the formative pluripotent state. Our work uncovers a pivotal role for FoxO TFs and AKT signalling in mechanisms establishing formative post-implantation pluripotency, a critical early embryonic cell fate transition.

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Section: Resultsmentioning

confidence: 83%

Section: Resultsmentioning

confidence: 99%

“…G Heatmap showing ESRRB signal in WT cells in 2iL, N48 and N96 (from Carbognin et al 2023) in a 1.5 kb window around the center of FoxO1 peak categories as defined in A.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

FoxO transcription factors actuate the formative pluripotency specific gene expression programme

Santini,

Kowald,

Sestini

et al. 2024

Preprint

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“…Alternatively, SMAD4 could promote epiblast maturation, defined here as the transition from a naïve to primed state which normally occurs in epiblast cells between preimplantation and post-implantation stages (Boroviak et al, 2015;Nichols and Smith, 2009). Epiblast maturation has been shown to be critical in formation of proamniotic cavity (Carbognin et al, 2023;Shahbazi et al, 2017). Other mechanisms are also proposed to play a role in embryonic cavitation such as apical domain maintenance (Meng et al, 2017), tight junction formation (Chan et al, 2019), cellular adhesion through ECM interactions (Liang et al, 2005;Sakai et al, 2003), and establishment of an osmotic gradient (Dumortier et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Smad4is essential for epiblast scaling and morphogenesis after implantation, but nonessential prior to implantation in the mouse

Kruger,

Frum,

Brumm

et al. 2024

Preprint

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Bone Morphogenic Protein (BMP) signaling plays an essential and highly conserved role in axial patterning in embryos of many externally developing animal species. However, in mammalian embryos, which develop inside the mother, early development includes an additional stage known as preimplantation. During preimplantation, the epiblast lineage is segregated from the extraembryonic lineages that enable implantation and development in utero. Yet, the requirement for BMP signaling in mouse preimplantation is imprecisely defined. We show that, in contrast to prior reports, BMP signaling (as reported by SMAD1/5/9 phosphorylation) is not detectable until implantation, when it is detected in the primitive endoderm - an extraembryonic lineage. Moreover, preimplantation development appears normal following deletion of maternal and zygotic Smad4, an essential effector of BMP signaling. In fact, mice lacking maternal Smad4 are viable. Finally, we uncover a new requirement for zygotic Smad4 in epiblast scaling and cavitation immediately after implantation, via a mechanism involving FGFR/ERK attenuation. Altogether, our results demonstrate no role for BMP4/SMAD4 in the first lineage decisions during mouse development. Rather, multi-pathway signaling among embryonic and extraembryonic cell types drives epiblast morphogenesis post-implantation.

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Esrrb guides naive pluripotent cells through the formative transcriptional programme

Cited by 12 publications

References 98 publications

FoxO transcription factors actuate the formative pluripotency specific gene expression programme

FoxO transcription factors actuate the formative pluripotency specific gene expression programme

Smad4is essential for epiblast scaling and morphogenesis after implantation, but nonessential prior to implantation in the mouse

Unraveling the impact of ZZZ3 on the mTOR/ribosome pathway in human embryonic stem cells homeostasis

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