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ZFP451-mediated SUMOylation of SATB2 drives embryonic stem cell differentiation

The establishment of cell fates involves alterations of transcription factor repertoires and repurposing of transcription factors by post-translational modifications. In embryonic stem cells (ESCs), the chromatin organizers SATB2 and SATB1 balance pluripotency and differentiation by activating and r...

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Autores principales: Antonio Urrutia, Gustavo, Ramachandran, Haribaskar, Cauchy, Pierre, Boo, Kyungjin, Ramamoorthy, Senthilkumar, Boller, Soeren, Dogan, Esen, Clapes, Thomas, Trompouki, Eirini, Torres-Padilla, Maria-Elena, Palvimo, Jorma J., Pichler, Andrea, Grosschedl, Rudolf
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336893/
https://www.ncbi.nlm.nih.gov/pubmed/34244292
http://dx.doi.org/10.1101/gad.345843.120
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author Antonio Urrutia, Gustavo
Ramachandran, Haribaskar
Cauchy, Pierre
Boo, Kyungjin
Ramamoorthy, Senthilkumar
Boller, Soeren
Dogan, Esen
Clapes, Thomas
Trompouki, Eirini
Torres-Padilla, Maria-Elena
Palvimo, Jorma J.
Pichler, Andrea
Grosschedl, Rudolf
author_facet Antonio Urrutia, Gustavo
Ramachandran, Haribaskar
Cauchy, Pierre
Boo, Kyungjin
Ramamoorthy, Senthilkumar
Boller, Soeren
Dogan, Esen
Clapes, Thomas
Trompouki, Eirini
Torres-Padilla, Maria-Elena
Palvimo, Jorma J.
Pichler, Andrea
Grosschedl, Rudolf
author_sort Antonio Urrutia, Gustavo
collection PubMed
description The establishment of cell fates involves alterations of transcription factor repertoires and repurposing of transcription factors by post-translational modifications. In embryonic stem cells (ESCs), the chromatin organizers SATB2 and SATB1 balance pluripotency and differentiation by activating and repressing pluripotency genes, respectively. Here, we show that conditional Satb2 gene inactivation weakens ESC pluripotency, and we identify SUMO2 modification of SATB2 by the E3 ligase ZFP451 as a potential driver of ESC differentiation. Mutations of two SUMO-acceptor lysines of Satb2 (Satb2(K →)(R)) or knockout of Zfp451 impair the ability of ESCs to silence pluripotency genes and activate differentiation-associated genes in response to retinoic acid (RA) treatment. Notably, the forced expression of a SUMO2-SATB2 fusion protein in either Satb2(K →)(R) or Zfp451(−/−) ESCs rescues, in part, their impaired differentiation potential and enhances the down-regulation of Nanog. The differentiation defect of Satb2(K →)(R) ESCs correlates with altered higher-order chromatin interactions relative to Satb2(wt) ESCs. Upon RA treatment of Satb2(wt) ESCs, SATB2 interacts with ZFP451 and the LSD1/CoREST complex and gains binding at differentiation genes, which is not observed in RA-treated Satb2(K →)(R) cells. Thus, SATB2 SUMOylation may contribute to the rewiring of transcriptional networks and the chromatin interactome of ESCs in the transition of pluripotency to differentiation.
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spelling pubmed-83368932022-02-01 ZFP451-mediated SUMOylation of SATB2 drives embryonic stem cell differentiation Antonio Urrutia, Gustavo Ramachandran, Haribaskar Cauchy, Pierre Boo, Kyungjin Ramamoorthy, Senthilkumar Boller, Soeren Dogan, Esen Clapes, Thomas Trompouki, Eirini Torres-Padilla, Maria-Elena Palvimo, Jorma J. Pichler, Andrea Grosschedl, Rudolf Genes Dev Research Paper The establishment of cell fates involves alterations of transcription factor repertoires and repurposing of transcription factors by post-translational modifications. In embryonic stem cells (ESCs), the chromatin organizers SATB2 and SATB1 balance pluripotency and differentiation by activating and repressing pluripotency genes, respectively. Here, we show that conditional Satb2 gene inactivation weakens ESC pluripotency, and we identify SUMO2 modification of SATB2 by the E3 ligase ZFP451 as a potential driver of ESC differentiation. Mutations of two SUMO-acceptor lysines of Satb2 (Satb2(K →)(R)) or knockout of Zfp451 impair the ability of ESCs to silence pluripotency genes and activate differentiation-associated genes in response to retinoic acid (RA) treatment. Notably, the forced expression of a SUMO2-SATB2 fusion protein in either Satb2(K →)(R) or Zfp451(−/−) ESCs rescues, in part, their impaired differentiation potential and enhances the down-regulation of Nanog. The differentiation defect of Satb2(K →)(R) ESCs correlates with altered higher-order chromatin interactions relative to Satb2(wt) ESCs. Upon RA treatment of Satb2(wt) ESCs, SATB2 interacts with ZFP451 and the LSD1/CoREST complex and gains binding at differentiation genes, which is not observed in RA-treated Satb2(K →)(R) cells. Thus, SATB2 SUMOylation may contribute to the rewiring of transcriptional networks and the chromatin interactome of ESCs in the transition of pluripotency to differentiation. Cold Spring Harbor Laboratory Press 2021-08-01 /pmc/articles/PMC8336893/ /pubmed/34244292 http://dx.doi.org/10.1101/gad.345843.120 Text en © 2021 Antonio Urrutia et al.; Published by Cold Spring Harbor Laboratory Press https://creativecommons.org/licenses/by-nc/4.0/This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Research Paper
Antonio Urrutia, Gustavo
Ramachandran, Haribaskar
Cauchy, Pierre
Boo, Kyungjin
Ramamoorthy, Senthilkumar
Boller, Soeren
Dogan, Esen
Clapes, Thomas
Trompouki, Eirini
Torres-Padilla, Maria-Elena
Palvimo, Jorma J.
Pichler, Andrea
Grosschedl, Rudolf
ZFP451-mediated SUMOylation of SATB2 drives embryonic stem cell differentiation
title ZFP451-mediated SUMOylation of SATB2 drives embryonic stem cell differentiation
title_full ZFP451-mediated SUMOylation of SATB2 drives embryonic stem cell differentiation
title_fullStr ZFP451-mediated SUMOylation of SATB2 drives embryonic stem cell differentiation
title_full_unstemmed ZFP451-mediated SUMOylation of SATB2 drives embryonic stem cell differentiation
title_short ZFP451-mediated SUMOylation of SATB2 drives embryonic stem cell differentiation
title_sort zfp451-mediated sumoylation of satb2 drives embryonic stem cell differentiation
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336893/
https://www.ncbi.nlm.nih.gov/pubmed/34244292
http://dx.doi.org/10.1101/gad.345843.120
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