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Phosphorylation of NANOG by casein kinase I regulates embryonic stem cell self‐renewal

The self‐renewal efficiency of mouse embryonic stem cells (ESCs) is determined by the concentration of the transcription factor NANOG. While NANOG binds thousands of sites in chromatin, the regulatory systems that control DNA binding are poorly characterised. Here, we show that NANOG is phosphorylat...

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Autores principales: Mullin, Nicholas P., Varghese, Joby, Colby, Douglas, Richardson, Julia M., Findlay, Greg M., Chambers, Ian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839479/
https://www.ncbi.nlm.nih.gov/pubmed/33107035
http://dx.doi.org/10.1002/1873-3468.13969
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author Mullin, Nicholas P.
Varghese, Joby
Colby, Douglas
Richardson, Julia M.
Findlay, Greg M.
Chambers, Ian
author_facet Mullin, Nicholas P.
Varghese, Joby
Colby, Douglas
Richardson, Julia M.
Findlay, Greg M.
Chambers, Ian
author_sort Mullin, Nicholas P.
collection PubMed
description The self‐renewal efficiency of mouse embryonic stem cells (ESCs) is determined by the concentration of the transcription factor NANOG. While NANOG binds thousands of sites in chromatin, the regulatory systems that control DNA binding are poorly characterised. Here, we show that NANOG is phosphorylated by casein kinase I, and identify target residues. Phosphomimetic substitutions at phosphorylation sites within the homeodomain (S130 and S131) have site‐specific functional effects. Phosphomimetic substitution of S130 abolishes DNA binding by NANOG and eliminates LIF‐independent self‐renewal. In contrast, phosphomimetic substitution of S131 enhances LIF‐independent self‐renewal, without influencing DNA binding. Modelling the DNA–homeodomain complex explains the disparate effects of these phosphomimetic substitutions. These results indicate how phosphorylation may influence NANOG homeodomain interactions that underpin ESC self‐renewal.
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spelling pubmed-78394792021-02-01 Phosphorylation of NANOG by casein kinase I regulates embryonic stem cell self‐renewal Mullin, Nicholas P. Varghese, Joby Colby, Douglas Richardson, Julia M. Findlay, Greg M. Chambers, Ian FEBS Lett Editor's Choice The self‐renewal efficiency of mouse embryonic stem cells (ESCs) is determined by the concentration of the transcription factor NANOG. While NANOG binds thousands of sites in chromatin, the regulatory systems that control DNA binding are poorly characterised. Here, we show that NANOG is phosphorylated by casein kinase I, and identify target residues. Phosphomimetic substitutions at phosphorylation sites within the homeodomain (S130 and S131) have site‐specific functional effects. Phosphomimetic substitution of S130 abolishes DNA binding by NANOG and eliminates LIF‐independent self‐renewal. In contrast, phosphomimetic substitution of S131 enhances LIF‐independent self‐renewal, without influencing DNA binding. Modelling the DNA–homeodomain complex explains the disparate effects of these phosphomimetic substitutions. These results indicate how phosphorylation may influence NANOG homeodomain interactions that underpin ESC self‐renewal. John Wiley and Sons Inc. 2020-11-18 2021-01 /pmc/articles/PMC7839479/ /pubmed/33107035 http://dx.doi.org/10.1002/1873-3468.13969 Text en © 2020 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies 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 Editor's Choice
Mullin, Nicholas P.
Varghese, Joby
Colby, Douglas
Richardson, Julia M.
Findlay, Greg M.
Chambers, Ian
Phosphorylation of NANOG by casein kinase I regulates embryonic stem cell self‐renewal
title Phosphorylation of NANOG by casein kinase I regulates embryonic stem cell self‐renewal
title_full Phosphorylation of NANOG by casein kinase I regulates embryonic stem cell self‐renewal
title_fullStr Phosphorylation of NANOG by casein kinase I regulates embryonic stem cell self‐renewal
title_full_unstemmed Phosphorylation of NANOG by casein kinase I regulates embryonic stem cell self‐renewal
title_short Phosphorylation of NANOG by casein kinase I regulates embryonic stem cell self‐renewal
title_sort phosphorylation of nanog by casein kinase i regulates embryonic stem cell self‐renewal
topic Editor's Choice
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839479/
https://www.ncbi.nlm.nih.gov/pubmed/33107035
http://dx.doi.org/10.1002/1873-3468.13969
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