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Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

Self‐renewal of embryonic stem cells (ESCs) cultured in LIF/fetal calf serum (FCS) is incomplete with some cells initiating differentiation. While this is reflected in heterogeneous expression of naive pluripotency transcription factors (TFs), the link between TF heterogeneity and differentiation is...

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Autores principales: Festuccia, Nicola, Halbritter, Florian, Corsinotti, Andrea, Gagliardi, Alessia, Colby, Douglas, Tomlinson, Simon R, Chambers, Ian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213284/
https://www.ncbi.nlm.nih.gov/pubmed/30275266
http://dx.doi.org/10.15252/embj.201695476
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author Festuccia, Nicola
Halbritter, Florian
Corsinotti, Andrea
Gagliardi, Alessia
Colby, Douglas
Tomlinson, Simon R
Chambers, Ian
author_facet Festuccia, Nicola
Halbritter, Florian
Corsinotti, Andrea
Gagliardi, Alessia
Colby, Douglas
Tomlinson, Simon R
Chambers, Ian
author_sort Festuccia, Nicola
collection PubMed
description Self‐renewal of embryonic stem cells (ESCs) cultured in LIF/fetal calf serum (FCS) is incomplete with some cells initiating differentiation. While this is reflected in heterogeneous expression of naive pluripotency transcription factors (TFs), the link between TF heterogeneity and differentiation is not fully understood. Here, we purify ESCs with distinct TF expression levels from LIF/FCS cultures to uncover early events during commitment from naïve pluripotency. ESCs carrying fluorescent Nanog and Esrrb reporters show Esrrb downregulation only in Nanog(low) cells. Independent Esrrb reporter lines demonstrate that Esrrb(negative) ESCs cannot effectively self‐renew. Upon Esrrb loss, pre‐implantation pluripotency gene expression collapses. ChIP‐Seq identifies different regulatory element classes that bind both OCT4 and NANOG in Esrrb(positive) cells. Class I elements lose NANOG and OCT4 binding in Esrrb(negative) ESCs and associate with genes expressed preferentially in naïve ESCs. In contrast, Class II elements retain OCT4 but not NANOG binding in ESRRB‐negative cells and associate with more broadly expressed genes. Therefore, mechanistic differences in TF function act cumulatively to restrict potency during exit from naïve pluripotency.
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spelling pubmed-62132842018-11-08 Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation Festuccia, Nicola Halbritter, Florian Corsinotti, Andrea Gagliardi, Alessia Colby, Douglas Tomlinson, Simon R Chambers, Ian EMBO J Articles Self‐renewal of embryonic stem cells (ESCs) cultured in LIF/fetal calf serum (FCS) is incomplete with some cells initiating differentiation. While this is reflected in heterogeneous expression of naive pluripotency transcription factors (TFs), the link between TF heterogeneity and differentiation is not fully understood. Here, we purify ESCs with distinct TF expression levels from LIF/FCS cultures to uncover early events during commitment from naïve pluripotency. ESCs carrying fluorescent Nanog and Esrrb reporters show Esrrb downregulation only in Nanog(low) cells. Independent Esrrb reporter lines demonstrate that Esrrb(negative) ESCs cannot effectively self‐renew. Upon Esrrb loss, pre‐implantation pluripotency gene expression collapses. ChIP‐Seq identifies different regulatory element classes that bind both OCT4 and NANOG in Esrrb(positive) cells. Class I elements lose NANOG and OCT4 binding in Esrrb(negative) ESCs and associate with genes expressed preferentially in naïve ESCs. In contrast, Class II elements retain OCT4 but not NANOG binding in ESRRB‐negative cells and associate with more broadly expressed genes. Therefore, mechanistic differences in TF function act cumulatively to restrict potency during exit from naïve pluripotency. John Wiley and Sons Inc. 2018-10-01 2018-11-02 /pmc/articles/PMC6213284/ /pubmed/30275266 http://dx.doi.org/10.15252/embj.201695476 Text en © 2018 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Festuccia, Nicola
Halbritter, Florian
Corsinotti, Andrea
Gagliardi, Alessia
Colby, Douglas
Tomlinson, Simon R
Chambers, Ian
Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation
title Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation
title_full Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation
title_fullStr Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation
title_full_unstemmed Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation
title_short Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation
title_sort esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213284/
https://www.ncbi.nlm.nih.gov/pubmed/30275266
http://dx.doi.org/10.15252/embj.201695476
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