Esrrb Conveys Naïve Pluripotent Cells Through The Formative Transcriptional Program

Carbognin, Elena; Carlini, Valentina; Panariello, Francesco; Perrera, Valentina; Malucelli, Cristina; Cesana, Marcella; Mutarelli, Margherita; Carissimo, Annamaria; Hackett, Jamie A.; Cacchiarelli, Davide; Martello, Graziano

doi:10.2139/ssrn.3659981

Cited by 7 publications

(15 citation statements)

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“…This confirms previous results highlighting how, during the early stages of ESC differentiation, the spontaneous downregulation of Esrrb instates a transcriptional state that displays analogies to primed pluripotency ( Festuccia et al, 2018a ). Importantly, extending previous reports ( Carbognin et al, 2020 ), we find that Esrrb and Nr5a2 sustain expression of key primed pluripotency regulators, in particular Otx2, Foxd3 and Etv4. Although the activity of several of these factors have been proposed to play a determining role in rewiring the pluripotency network during the dismantling of naïve pluripotency ( Buecker et al, 2014 ; Chen et al, 2018 ; Respuela et al, 2016 ; Yang et al, 2014 ), the global transcriptional changes we observe despite their attenuated expression suggest that the loss of naïve TFs, and thus of cooperative interactions, plays an equally determinant role in driving the transition between pluripotent states.…”

Section: Discussionsupporting

confidence: 91%

“…4 D, Pearson correlation coefficients: left panel Epi E4.5/Epi E5.5: 0.42, ICM/Epi E5.5: 0.36, from Boroviak et al, 2015; right panel Epi E4.5/Epi E5.5 0.36, from Argelaguet et al, 2019). Yet, as recently reported ( Carbognin et al, 2020 ), Esrrb activity not only globally opposes, but also contributes to preparing the rewiring of the pluripotency network: Esrrb appears to license expression of specific regulators of formative/primed pluripotency. Crucially, also in this context Esrrb and Nr5a2 display clear synergy, as shown by the complete silencing of Otx2 , and the downregulation of Foxd3 , Utf1 and Etv4 following loss of either or, more pronouncedly, both TFs ( Fig.…”

Section: Resultssupporting

confidence: 52%

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The combined action of Esrrb and Nr5a2 is essential for murine naïve pluripotency

et al. 2021

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The maintenance of pluripotency in mouse embryonic stem cells (ESCs) is governed by the action of an interconnected network of transcription factors. Among them, only Oct4 and Sox2 have been shown to be strictly required for the self-renewal of ESCs and pluripotency, particularly in culture conditions where differentiation cues are chemically inhibited. Here, we report that the conjunct activity of two orphan nuclear receptors, Esrrb and Nr5a2, parallels the importance of that of Oct4 and Sox2 in naïve ESCs. By occupying a large common set of regulatory elements, these two factors control the binding of Oct4, Sox2 and Nanog to DNA. Consequently, in their absence the pluripotency network collapses and the transcriptome is substantially deregulated, leading to the differentiation of ESCs. Altogether, this work identifies orphan nuclear receptors, previously thought to be performing supportive functions, as a new set of core regulators of naïve pluripotency.

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Section: Discussionsupporting

confidence: 91%

Section: Resultssupporting

confidence: 52%

The combined action of Esrrb and Nr5a2 is essential for murine naïve pluripotency

et al. 2021

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“…To ground the model within biologically plausible parameters, I have populated the model using rate constants for the transcription factor Nanog (figure 1 a ). Nanog clearance is the rate limiting factor during exit from the embryonic stem cell state in mouse [26] and overexpression significantly delays/impairs the transition to a differentiated state [27,28]. Therefore, it is likely that the rate parameters of Nanog are optimized for transitions and are a good starting point.…”

Section: Effect Of Synthesis and Degradation Rates On Transitionsmentioning

confidence: 99%

Control of cell state transitions by post-transcriptional regulation

Mulas

2024

Phil. Trans. R. Soc. B

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Cell state transitions are prevalent in biology, playing a fundamental role in development, homeostasis and repair. Dysregulation of cell state transitions can lead to or occur in a wide range of diseases. In this letter, I explore and highlight the role of post-transcriptional regulatory mechanisms in determining the dynamics of cell state transitions. I propose that regulation of protein levels after transcription provides an under-appreciated regulatory route to obtain fast and sharp transitions between distinct cell states. This article is part of a discussion meeting issue ‘Causes and consequences of stochastic processes in development and disease’.

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“…When 2i and LIF (2iLIF) are removed and replaced instead by stimulation with bFGF, the cells exit the naive state of pluripotency and initiate differentiation into the next developmental state, often referred to as formative pluripotency [7][8][9][10] . Within 24-36hrs the cells downregulate the naive pluripotent gene expression profile and activate a novel gene expression profile [11][12][13][14][15] , thereby committing to differentiation irreversibly.…”

Section: Introductionmentioning

confidence: 99%

The asynchrony in the exit from naive pluripotency cannot be explained by differences in the cell cycle phase

Jayaram,

Romeike,

Buecker

2023

Preprint

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Development is characterized by consecutive cell state transitions that build on each other and ultimately lead to the generation of the numerous different cell types found in the organism. During each of these transitions, cells change their gene expression profiles and take on new identities. Cell state transitions have to be tightly coordinated with proliferation to ensure simultaneous growth and differentiation. The exit from naive pluripotency is an ideal model system to study the temporal coordination of proliferation and differentiation. Individual cells initiate differentiation earlier compared to others, thereby leading to an asynchronous exit from naive pluripotency. One of the major differences among the cells of the starting population of mouse embryonic stem cells (mESCs) is the cell cycle status, and could therefore be an underlying cause of the differences in the onset of the exit from naive pluripotency. However, through a comprehensive analysis including single-cell RNA sequencing (scRNA-seq), cell cycle synchronization, and perturbation experiments, we demonstrate here that the cell cycle phase at the initiation of differentiation does not influence the timing of the exit from naive pluripotency.

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Esrrb Conveys Naïve Pluripotent Cells Through The Formative Transcriptional Program

Cited by 7 publications

References 0 publications

The combined action of Esrrb and Nr5a2 is essential for murine naïve pluripotency

The combined action of Esrrb and Nr5a2 is essential for murine naïve pluripotency

Control of cell state transitions by post-transcriptional regulation

The asynchrony in the exit from naive pluripotency cannot be explained by differences in the cell cycle phase

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