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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
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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. |
format | Online Article Text |
id | pubmed-6213284 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
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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