Dynamic lineage priming is driven via direct enhancer regulation by ERK

Hamilton, William B.; Mosesson, Yaron; Monteiro, Rita S.; Emdal, Kristina B.; Knudsen, Teresa E.; Francavilla, Chiara; Barkai, Naama; Olsen, Jesper V.; Brickman, Joshua M.

doi:10.1038/s41586-019-1732-z

Cited by 71 publications

(78 citation statements)

References 44 publications

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“…In our mouse nEnd paper (Anderson et al, 2017), we found that there was a correlation between enhancer accessibility and definitive endoderm versus primitive endoderm lineage differentiation. This is a remarkably similar idea to our recent thoughts on specificity of FGF/ERK signalling (Hamilton et al, 2019). Here, we found that ERK directly regulates enhancers, but that the activity of ERK on enhancers is likely to depend on prebound transcription factors, that don't in themselves activate transcription, but prepare the available differentiation trajectories a cell can take when exposed to a signal.…”

supporting

confidence: 84%

The people behind the papers – Madeleine Linneberg-Agerholm, Yan Fung Wong and Josh Brickman

2019

Development

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Our understanding of lineage decisions in early human development has been greatly aided by embryonic stem cell lines, which avoid many of the practical and ethical difficulties of in vivo material. A new paper in Development exploits naïve human embryonic stem cells to generate in vitro models for the extra-embryonic endoderm. We caught up with first authors Madeleine Linneberg-Agerholm and Yan Fung Wong, and their supervisor Josh Brickman, Professor of Stem Cell and Developmental Biology at the Novo Nordisk Foundation Center for Stem Cell Biology (DanStem) in Copenhagen, to hear more about the work. Josh, can you give us your scientific biography and the questions your lab is trying to answer?

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supporting

confidence: 84%

The people behind the papers – Madeleine Linneberg-Agerholm, Yan Fung Wong and Josh Brickman

2019

Development

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“…PD also contributes to inducing resistance to suppression of Pol2 pause release in 2iL possibly by inducing Nanog mRNA and stabilizing NANOG protein ( 50 ). The former effect might be caused by preventing extracellular signal–regulated kinase–mediated phosphorylation and dissociation of coregulators including MED24 from Pol2-containing complexes at the Nanog locus ( 51 ). As opposed to pluripotency genes, proliferation genes are not bound by β-catenin and, thus, remain very sensitive to suppression of Pol2 pause release in 2iL.…”

Section: Discussionmentioning

confidence: 99%

β-Catenin safeguards the ground state of mousepluripotency by strengthening the robustness of the transcriptional apparatus

et al. 2020

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Mouse embryonic stem cells cultured with MEK (mitogen-activated protein kinase kinase) and GSK3 (glycogen synthase kinase 3) inhibitors (2i) more closely resemble the inner cell mass of preimplantation blastocysts than those cultured with SL [serum/leukemia inhibitory factor (LIF)]. The transcriptional mechanisms governing this pluripotent ground state are unresolved. Release of promoter-proximal paused RNA polymerase II (Pol2) is a multistep process necessary for pluripotency and cell cycle gene transcription in SL. We show that β-catenin, stabilized by GSK3 inhibition in medium with 2i, supplies transcriptional coregulators at pluripotency loci. This selectively strengthens pluripotency loci and renders them addicted to transcription initiation for productive gene body elongation in detriment to Pol2 pause release. By contrast, cell cycle genes are not bound by β-catenin, and proliferation/self-renewal remains tightly controlled by Pol2 pause release under 2i conditions. Our findings explain how pluripotency is reinforced in the ground state and also provide a general model for transcriptional resilience/adaptation upon network perturbation in other contexts.

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“…Amongst the pluripotency genes downregulated by ERK in ESCs, Nanog might perform a central function, given that ERK directly regulates expression (Hamilton and Brickman, 2014) and phosphorylates this TF (Kim et al, 2014), and that Nanog contrasts the function of FGF/ERK signalling in inducing primitive endoderm specification during early development (Chazaud et al, 2006;Frankenberg et al, 2011;Nichols et al, 2009). Nonetheless, Esrrb could also play an important part in mediating the effects of ERK inhibition: ERK has been shown to phosphorylate and control the activity of subunits of the Mediator complex (Hamilton et al, 2019), that Esrrb deploys at enhancers of the pluripotency network to activate transcription (Bell et al, 2020;Percharde et al, 2012). It remains to be addressed whether Nr5a2 displays a similar ability to interact with the transcriptional machinery in ESCs.…”

Section: Discussionmentioning

confidence: 99%

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

Festuccia

Owens

Chervova

et al. 2020

Preprint

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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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Dynamic lineage priming is driven via direct enhancer regulation by ERK

Cited by 71 publications

References 44 publications

The people behind the papers – Madeleine Linneberg-Agerholm, Yan Fung Wong and Josh Brickman

The people behind the papers – Madeleine Linneberg-Agerholm, Yan Fung Wong and Josh Brickman

β-Catenin safeguards the ground state of mousepluripotency by strengthening the robustness of the transcriptional apparatus

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

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