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

Festuccia, Nicola; Owens, Nick; Chervova, Almira; Dubois, Agnès; Navarro, Pablo

doi:10.1242/dev.199604

Cited by 34 publications

(79 citation statements)

References 91 publications

(172 reference statements)

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“…1G and 1H, scheme (i)). These findings are consistent with a function of Nr5a2 in maintaining naïve pluripotency in mouse ES cells ( 26 ). Intriguingly, embryos treated with SR1848 from 36 hpf (2-cell stage) had a less severe phenotype than those treated from 6 hpf (Fig.…”

Section: Main Textsupporting

confidence: 89%

“…S1F). The CA version of motif 1 contains the consensus sequences for orphan nuclear receptors Nr5a2 (T CA AGG C CA, hereafter Nr5a2 motif) and Esrrb (T CA AGG T CA, hereafter Esrrb motif) and nuclear hormone receptor “retinoic acid receptor gamma” (Rarg) (AGGT CA AGGTCA) ( 26, 27 ). Given that Rarg is not essential for ZGA since Rarg -/- females are fertile ( 18 ), we focused on the orphan nuclear receptors.…”

Section: Main Textmentioning

confidence: 99%

“…Esrrb, and to a lesser extent Nr5a2, are expressed in ES cells ( 26, 40 ). To determine if these transcription factors are recruited to distinct cREs in totipotent 2-cell embryos vs. pluripotent ES cells, we examined published data ( 40, 41 ).…”

Section: Main Textmentioning

confidence: 99%

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Zygotic genome activation by the totipotency pioneer factor Nr5a2

Gassler

Kobayashi

Gáspár

et al. 2022

Preprint

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Life begins with a switch in genetic control from the maternal to the embryonic genome during zygotic genome activation (ZGA) in totipotent embryos. Despite its importance, the essential regulators of ZGA remain largely unknown in mammals. Based on de novo motif searches, we identified the orphan nuclear receptor Nr5a2 as a key activator of major ZGA in mouse embryos. Nr5a2 binds to its motif within a subtype of SINE B1/Alu transposable elements found in cis-regulatory regions of ZGA genes. Chemical inhibition suggests that 72% of ZGA genes are regulated by Nr5a2 and potentially other orphan nuclear family receptors. Consistent with a role in ZGA, Nr5a2 is required for progression beyond the 2-cell stage. Nr5a2 promotes chromatin accessibility during ZGA and binds to entry/exit sites of nucleosomal DNA in vitro. We conclude that Nr5a2 is an essential pioneer factor that distinctly regulates totipotency and pluripotency during mammalian development.One-Sentence SummaryNr5a2 is an essential pioneer transcription factor that activates expression of zygotic genes in mouse embryos.

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Section: Main Textsupporting

confidence: 89%

Section: Main Textmentioning

confidence: 99%

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Zygotic genome activation by the totipotency pioneer factor Nr5a2

Gassler

Kobayashi

Gáspár

et al. 2022

Preprint

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“…Differentiation is only abolished by simultaneous genetic deletion of three complementary drivers (Kalkan et al 2019). Furthermore, the naive pluripotency network is supported by functionally overlapping factors of the same orphan nuclear receptor family (Festuccia et al 2021). We therefore speculate that cooperativity and redundancy between two or more factors are ensuring proper execution of this cell state transition, and that screening approaches should be adapted to this in the future.…”

Section: Discussionmentioning

confidence: 92%

Stem cell specific interferon stimulated gene expression is regulated by the formative pluripotency network through IRF1

Romeike

Spach

Huber

et al. 2021

Preprint

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Stem cells intrinsically express a subset of genes which are normally associated with interferon stimulation, and thus the innate immunity response. Expression of these interferon stimulated genes (ISG) in stem cells is independent of external stimuli such as viral infection. Here we show that the interferon regulatory factor 1, Irf1, is directly controlled by the murine formative pluripotency gene regulatory network and therefore upregulated in the transition from naive to formative pluripotency. IRF1 in turn binds to regulatory regions of a conserved set of ISGs and is required for their faithful expression in formative pluripotent cells. IRF1 also binds to an enhancer of the formative pluripotency transcription factor Oct6 and is partially required for upregulation of Oct6. IRF1 therefore acts as a link between the formative pluripotency network and the regulation of innate immunity genes in formative pluripotency.

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“…TF binding sites were previously reported 11,19,22 . Fisher-exact tests to assess gene-TF proximity enrichments were performed as previously described 11,19,22,35 . ChIP-seq enrichments were calculated with bamsignals.…”

Section: Methodsmentioning

confidence: 99%

Mitotic bookmarking by CTCF controls selected genes during the fast post-mitotic genome reactivation of ES cells

Chervova

Festuccia

Dubois

et al. 2022

Preprint

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Mitosis leads to a global downregulation of transcription that then needs to be efficiently restored. In somatic cells, this is mediated by a transient hyper-active state that first leads to the reactivation of genes necessary to rebuild the interphasic cell and then of those executing specific cell functions. Here, we hypothesized that cells displaying rapid cell cycles may display accelerated gene reactivation dynamics. To test this, we focused on mouse Embryonic Stem (ES) cells, which have a short cell cycle and spend a minor time in G1. Compared to previous studies, we observed a uniquely fast global reactivation, which displays little specificity towards housekeeping versus cell identity genes. Such lack of specificity may enable the restoration of the entirety of regulatory functions before the onset of DNA replication. Genes displaying the fastest reactivation dynamics are associated with binding of CTCF, a transcription factor that largely maintains binding to its targets on DNA during mitosis. Nevertheless, we show that the post-mitotic global burst is robust and largely insensitive to CTCF depletion. There are, however, around 350 genes that respond to CTCF depletion rapidly after mitotic exit. Remarkably, these are characterised by promoter-proximal mitotic bookmarking by CTCF. We propose that the structure of the cell cycle imposes distinct constrains to post-mitotic gene reactivation dynamics in different cell types, via mechanisms that are yet to be identified but that can be modulated by mitotic bookmarking factors.

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

Cited by 34 publications

References 91 publications

Zygotic genome activation by the totipotency pioneer factor Nr5a2

Zygotic genome activation by the totipotency pioneer factor Nr5a2

Stem cell specific interferon stimulated gene expression is regulated by the formative pluripotency network through IRF1

Mitotic bookmarking by CTCF controls selected genes during the fast post-mitotic genome reactivation of ES cells

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