Cargando…

A tight control of Rif1 by Oct4 and Smad3 is critical for mouse embryonic stem cell stability

Prolonged culture of embryonic stem cells (ESCs) leads them to adopt embryonal carcinoma cell features, creating enormous dangers for their further application. The mechanism involved in ESC stability has not, however, been extensively studied. We previously reported that SMAD family member 3 (Smad3...

Descripción completa

Detalles Bibliográficos
Autores principales: Li, P, Ma, X, Adams, I R, Yuan, P
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669749/
https://www.ncbi.nlm.nih.gov/pubmed/25569105
http://dx.doi.org/10.1038/cddis.2014.551
_version_ 1782404157764796416
author Li, P
Ma, X
Adams, I R
Yuan, P
author_facet Li, P
Ma, X
Adams, I R
Yuan, P
author_sort Li, P
collection PubMed
description Prolonged culture of embryonic stem cells (ESCs) leads them to adopt embryonal carcinoma cell features, creating enormous dangers for their further application. The mechanism involved in ESC stability has not, however, been extensively studied. We previously reported that SMAD family member 3 (Smad3) has an important role in maintaining mouse ESC stability, as depletion of Smad3 results in cancer cell-like properties in ESCs and Smad3−/− ESCs are prone to grow large, malignant teratomas. To understand how Smad3 contributes to ESC stability, we performed microarray analysis to compare the transcriptome of wild-type and Smad3−/− ESCs. We found that Rif1 (RAP1-associated protein 1), a factor important for genomic stability, is significantly upregulated in Smad3−/− ESCs. The expression level of Rif1 needs to be tightly controlled in ESCs, as a low level of Rif1 is associated with ESC differentiation, but a high level of Rif1 is linked to ESC transformation. In ESCs, Oct4 activates Rif1, whereas Smad3 represses its expression. Oct4 recruits Smad3 to bind to Rif1 promoter, but Smad3 joining facilitates the loading of a polycomb complex that generates a repressive epigenetic modification on Rif1 promoter, and thus maintains the expression of Rif1 at a proper level in ESCs. Interestingly, Rif1 short hairpin RNA (shRNA)-transduced Smad3−/− ESCs showed less malignant properties than the control shRNA-transduced Smad3−/− ESCs, suggesting a critical role of Rif1 in maintaining the stability of ESCs during proliferation.
format Online
Article
Text
id pubmed-4669749
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-46697492015-12-08 A tight control of Rif1 by Oct4 and Smad3 is critical for mouse embryonic stem cell stability Li, P Ma, X Adams, I R Yuan, P Cell Death Dis Original Article Prolonged culture of embryonic stem cells (ESCs) leads them to adopt embryonal carcinoma cell features, creating enormous dangers for their further application. The mechanism involved in ESC stability has not, however, been extensively studied. We previously reported that SMAD family member 3 (Smad3) has an important role in maintaining mouse ESC stability, as depletion of Smad3 results in cancer cell-like properties in ESCs and Smad3−/− ESCs are prone to grow large, malignant teratomas. To understand how Smad3 contributes to ESC stability, we performed microarray analysis to compare the transcriptome of wild-type and Smad3−/− ESCs. We found that Rif1 (RAP1-associated protein 1), a factor important for genomic stability, is significantly upregulated in Smad3−/− ESCs. The expression level of Rif1 needs to be tightly controlled in ESCs, as a low level of Rif1 is associated with ESC differentiation, but a high level of Rif1 is linked to ESC transformation. In ESCs, Oct4 activates Rif1, whereas Smad3 represses its expression. Oct4 recruits Smad3 to bind to Rif1 promoter, but Smad3 joining facilitates the loading of a polycomb complex that generates a repressive epigenetic modification on Rif1 promoter, and thus maintains the expression of Rif1 at a proper level in ESCs. Interestingly, Rif1 short hairpin RNA (shRNA)-transduced Smad3−/− ESCs showed less malignant properties than the control shRNA-transduced Smad3−/− ESCs, suggesting a critical role of Rif1 in maintaining the stability of ESCs during proliferation. Nature Publishing Group 2015-01 2015-01-08 /pmc/articles/PMC4669749/ /pubmed/25569105 http://dx.doi.org/10.1038/cddis.2014.551 Text en Copyright © 2015 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International Licence. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons licence, users will need to obtain permission from the licence holder to reproduce the material. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0
spellingShingle Original Article
Li, P
Ma, X
Adams, I R
Yuan, P
A tight control of Rif1 by Oct4 and Smad3 is critical for mouse embryonic stem cell stability
title A tight control of Rif1 by Oct4 and Smad3 is critical for mouse embryonic stem cell stability
title_full A tight control of Rif1 by Oct4 and Smad3 is critical for mouse embryonic stem cell stability
title_fullStr A tight control of Rif1 by Oct4 and Smad3 is critical for mouse embryonic stem cell stability
title_full_unstemmed A tight control of Rif1 by Oct4 and Smad3 is critical for mouse embryonic stem cell stability
title_short A tight control of Rif1 by Oct4 and Smad3 is critical for mouse embryonic stem cell stability
title_sort tight control of rif1 by oct4 and smad3 is critical for mouse embryonic stem cell stability
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669749/
https://www.ncbi.nlm.nih.gov/pubmed/25569105
http://dx.doi.org/10.1038/cddis.2014.551
work_keys_str_mv AT lip atightcontrolofrif1byoct4andsmad3iscriticalformouseembryonicstemcellstability
AT max atightcontrolofrif1byoct4andsmad3iscriticalformouseembryonicstemcellstability
AT adamsir atightcontrolofrif1byoct4andsmad3iscriticalformouseembryonicstemcellstability
AT yuanp atightcontrolofrif1byoct4andsmad3iscriticalformouseembryonicstemcellstability
AT lip tightcontrolofrif1byoct4andsmad3iscriticalformouseembryonicstemcellstability
AT max tightcontrolofrif1byoct4andsmad3iscriticalformouseembryonicstemcellstability
AT adamsir tightcontrolofrif1byoct4andsmad3iscriticalformouseembryonicstemcellstability
AT yuanp tightcontrolofrif1byoct4andsmad3iscriticalformouseembryonicstemcellstability