Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells

Shinji Masui; Yuhki Nakatake; Yayoi Toyooka; Daisuke Shimosato; Rika Yagi; Kazue Takahashi; Hitoshi Okochi; Akihiko Okuda; Ryo Matoba; Alexei A. Sharov; Minoru S.H. Ko; Hitoshi Niwa

doi:10.1038/ncb1589

Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells

Shinji Masui, Yuhki Nakatake, Yayoi Toyooka, Daisuke Shimosato, Rika Yagi, Kazue Takahashi, Hitoshi Okochi, Akihiko Okuda, Ryo Matoba, Alexei A. Sharov, Minoru S.H. Ko, Hitoshi Niwa

Research output: Contribution to journal › Article › peer-review

890 Citations (Scopus)

Abstract

The pluripotency of embryonic stem (ES) cells is thought to be maintained by a few key transcription factors, including Oct3/4 and Sox2. The function of Oct3/4 in ES cells has been extensively characterized, but that of Sox2 has yet to be determined. Sox2 can act synergistically with Oct3/4 in vitro to activate Oct-Sox enhancers, which regulate the expression of pluripotent stem cell-specific genes, including Nanog, Oct3/4 and Sox2 itself. These findings suggest that Sox2 is required by ES cells for its Oct-Sox enhancer activity. Using inducible Sox2-null mouse ES cells, we show that Sox2 is dispensable for the activation of these Oct-Sox enhancers. In contrast, we demonstrate that Sox2 is necessary for regulating multiple transcription factors that affect Oct3/4 expression and that the forced expression of Oct3/4 rescues the pluripotency of Sox2-null ES cells. These results indicate that the essential function of Sox2 is to stabilize ES cells in a pluripotent state by maintaining the requisite level of Oct3/4 expression.

Original language	English
Pages (from-to)	625-635
Number of pages	11
Journal	Nature Cell Biology
Volume	9
Issue number	6
DOIs	https://doi.org/10.1038/ncb1589
Publication status	Published - 2007 Jun
Externally published	Yes

ASJC Scopus subject areas

Cell Biology

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10.1038/ncb1589

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@article{c6dade648eec4af9b497ee0463606310,

title = "Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells",

abstract = "The pluripotency of embryonic stem (ES) cells is thought to be maintained by a few key transcription factors, including Oct3/4 and Sox2. The function of Oct3/4 in ES cells has been extensively characterized, but that of Sox2 has yet to be determined. Sox2 can act synergistically with Oct3/4 in vitro to activate Oct-Sox enhancers, which regulate the expression of pluripotent stem cell-specific genes, including Nanog, Oct3/4 and Sox2 itself. These findings suggest that Sox2 is required by ES cells for its Oct-Sox enhancer activity. Using inducible Sox2-null mouse ES cells, we show that Sox2 is dispensable for the activation of these Oct-Sox enhancers. In contrast, we demonstrate that Sox2 is necessary for regulating multiple transcription factors that affect Oct3/4 expression and that the forced expression of Oct3/4 rescues the pluripotency of Sox2-null ES cells. These results indicate that the essential function of Sox2 is to stabilize ES cells in a pluripotent state by maintaining the requisite level of Oct3/4 expression.",

author = "Shinji Masui and Yuhki Nakatake and Yayoi Toyooka and Daisuke Shimosato and Rika Yagi and Kazue Takahashi and Hitoshi Okochi and Akihiko Okuda and Ryo Matoba and Sharov, {Alexei A.} and Ko, {Minoru S.H.} and Hitoshi Niwa",

note = "Funding Information: We thank H. Bujard (University of Heidelberg) for providing the plasmid pUHD-tetR/VP16(FF); I. R. Lemischka (Princeton University) for the Sox2 knockdown cell lines; S. Miyagi for RNA samples from E11.5 embryos; and Y. Piao for microarray hybridization. This work was supported in part by grant-in-aids for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to S.M.) and by a RIKEN grant and grants for the 21st Century COE Program, from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and the Leading Project (to H.N.). H.N. also received funding from the CREST program of the Japan Science and Technology Agency. The work was also supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health.",

year = "2007",

month = jun,

doi = "10.1038/ncb1589",

language = "English",

volume = "9",

pages = "625--635",

journal = "Nature Cell Biology",

issn = "1465-7392",

publisher = "Nature Publishing Group",

number = "6",

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T1 - Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells

AU - Masui, Shinji

AU - Nakatake, Yuhki

AU - Toyooka, Yayoi

AU - Shimosato, Daisuke

AU - Yagi, Rika

AU - Takahashi, Kazue

AU - Okochi, Hitoshi

AU - Okuda, Akihiko

AU - Matoba, Ryo

AU - Sharov, Alexei A.

AU - Ko, Minoru S.H.

AU - Niwa, Hitoshi

N1 - Funding Information: We thank H. Bujard (University of Heidelberg) for providing the plasmid pUHD-tetR/VP16(FF); I. R. Lemischka (Princeton University) for the Sox2 knockdown cell lines; S. Miyagi for RNA samples from E11.5 embryos; and Y. Piao for microarray hybridization. This work was supported in part by grant-in-aids for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to S.M.) and by a RIKEN grant and grants for the 21st Century COE Program, from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and the Leading Project (to H.N.). H.N. also received funding from the CREST program of the Japan Science and Technology Agency. The work was also supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health.

PY - 2007/6

Y1 - 2007/6

N2 - The pluripotency of embryonic stem (ES) cells is thought to be maintained by a few key transcription factors, including Oct3/4 and Sox2. The function of Oct3/4 in ES cells has been extensively characterized, but that of Sox2 has yet to be determined. Sox2 can act synergistically with Oct3/4 in vitro to activate Oct-Sox enhancers, which regulate the expression of pluripotent stem cell-specific genes, including Nanog, Oct3/4 and Sox2 itself. These findings suggest that Sox2 is required by ES cells for its Oct-Sox enhancer activity. Using inducible Sox2-null mouse ES cells, we show that Sox2 is dispensable for the activation of these Oct-Sox enhancers. In contrast, we demonstrate that Sox2 is necessary for regulating multiple transcription factors that affect Oct3/4 expression and that the forced expression of Oct3/4 rescues the pluripotency of Sox2-null ES cells. These results indicate that the essential function of Sox2 is to stabilize ES cells in a pluripotent state by maintaining the requisite level of Oct3/4 expression.

AB - The pluripotency of embryonic stem (ES) cells is thought to be maintained by a few key transcription factors, including Oct3/4 and Sox2. The function of Oct3/4 in ES cells has been extensively characterized, but that of Sox2 has yet to be determined. Sox2 can act synergistically with Oct3/4 in vitro to activate Oct-Sox enhancers, which regulate the expression of pluripotent stem cell-specific genes, including Nanog, Oct3/4 and Sox2 itself. These findings suggest that Sox2 is required by ES cells for its Oct-Sox enhancer activity. Using inducible Sox2-null mouse ES cells, we show that Sox2 is dispensable for the activation of these Oct-Sox enhancers. In contrast, we demonstrate that Sox2 is necessary for regulating multiple transcription factors that affect Oct3/4 expression and that the forced expression of Oct3/4 rescues the pluripotency of Sox2-null ES cells. These results indicate that the essential function of Sox2 is to stabilize ES cells in a pluripotent state by maintaining the requisite level of Oct3/4 expression.

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EP - 635

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 6

ER -

Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells

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