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

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

doi:10.1038/ncb1589

Cited by 1,086 publications

(969 citation statements)

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“…In support of this view, chromatin immunoprecipitation-seq studies show that Sox2 can bind directly to the promoter of Dnmt3b [50,51], and a dramatic decrease of Zfp459 expression is observed after Sox2 knockout [52]. Our data also reveal that the methylation process begins immediately after Sox2 overexpression, while the induction of endogenous Nanog begins much later.…”

Section: Discussionsupporting

confidence: 79%

Two-Phase Analysis of Molecular Pathways Underlying Induced Pluripotent Stem Cell Induction

Lin

Perez

Lei³

et al. 2011

Stem Cells

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Induced pluripotent stem cells (iPSCs) can be reprogrammed from adult somatic cells by transduction with Oct4, Sox2, Klf4, and c-Myc, but the molecular cascades initiated by these factors remain poorly understood. Impeding their elucidation is the stochastic nature of the iPS induction process, which results in heterogeneous cell populations. Here we have synchronized the reprogramming process by a two-phase induction: an initial stable intermediate phase following transduction with Oct4, Klf4, and c-Myc, and a final iPS phase following overexpression of Sox2. This approach has enabled us to examine temporal gene expression profiles, permitting the identification of Sox2 downstream genes critical for induction. Furthermore, we have validated the feasibility of our new approach by using it to confirm that downregulation of transforming growth factor b signaling by Sox2 proves essential to the reprogramming process. Thus, we present a novel means for dissecting the details underlying the induction of iPSCs, an approach with significant utility in this arena and the potential for wide-ranging implications in the study of other reprogramming mechanisms. STEM

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Section: Discussionsupporting

confidence: 79%

Two-Phase Analysis of Molecular Pathways Underlying Induced Pluripotent Stem Cell Induction

Lin

Perez

Lei³

et al. 2011

Stem Cells

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“…For a third group of genes, we obtained reproducible reverse transcriptase-PCR evaluation ( Figure 3). In particular, we detected the expression of OCT3, NANOG and KLF4, which are part of the core transcriptional circuitry for regulation of embryonic stem cell properties (Matoba et al, 2006;Masui et al, 2007). Of great interest is that BRG1 downregulation completely abolished NANOG expression ( Figure 3).…”

Section: Resultsmentioning

confidence: 99%

The BRG1 ATPase of chromatin remodeling complexes is involved in modulation of mesenchymal stem cell senescence through RB–P53 pathways

et al. 2010

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We focused our attention on brahma-related gene 1 (BRG1), the ATPase subunit of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex, and analyzed its role in mesenchymal stem cell (MSC) biology. We hypothesized that deviation from the correct concentration of these proteins, which act at the highest level of gene regulation, may be deleterious for cells. We wanted to know what would happen if a cell had to cope with altered regulation of gene expression, either by upregulation or downregulation of BRG1. We assumed that cells would try to restore homeostasis or, alternatively, that the event could trigger senescence/apoptosis phenomena. To this end, in MSCs, we silenced BRG1gene. Knockdown of BRG1 expression induced a significant increase in senescent cells and decrease in apoptotic cells. It is interesting that BRG1 downregulation also induced an increase in heterochromatin. At the molecular level, these phenomena were associated with activation of retinoblastoma-like protein 2 (RB2)/P130-and P53-related pathways. Senescence was accompanied by reduced expression of some stemness-related genes. This is consistent with our previous research, which showed that BRG1 upregulation by ectopic expression also induced senescence processes. Together, these data suggest that BRG1 belongs to a class of genes whose expression is tightly regulated; hence, subtle alterations in BRG1 activity seem to negatively affect mechanisms regulating chromatin status and, in turn, impair cellular physiology.

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“…The second reprogramming factor, Sox2, forms a complex with Oct4 to regulate the transcription of key pluripotency genes including Oct4, Sox2 and Nanog (Masui et al, 2007). However, it is not absolutely required for pluripotency or reprogramming.…”

Section: Molecular Mechanism Of Reprogramming To Pluripotency the Funmentioning

confidence: 99%

“…However, it is not absolutely required for pluripotency or reprogramming. In Sox2 null ES cells, overexpression of Oct4 was able to maintain the undifferentiated state (Masui et al, 2007). During reprogramming of mouse fibroblast cells, TGFβ inhibitors can replace Sox2 by inducing Nanog and cMyc expression (Ichida et al, 2009;Maherali and Hochedlinger, 2009).…”

Section: Molecular Mechanism Of Reprogramming To Pluripotency the Funmentioning

confidence: 99%

Mechanism and methods to induce pluripotency

Wang

2011

Protein Cell

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Pluripotent stem cells are able to self-renew indefinitely and differentiate into all types of cells in the body. They can thus be an inexhaustible source for future cell transplantation therapy to treat degenerative diseases which currently have no cure. However, non-autologous cells will cause immune rejection. Induced pluripotent stem cell (iPSC) technology can convert somatic cells to the pluripotent state, and therefore offers a solution to this problem. Since the first generation of iPSCs, there has been an explosion of relevant research, from which we have learned much about the genetic networks and epigenetic landscape of pluripotency, as well as how to manipulate genes, epigenetics, and microRNAs to obtain iPSCs. In this review, we focus on the mechanism of cellular reprogramming and current methods to induce pluripotency. We also highlight new problems emerging from iPSCs. Better understanding of the fundamental mechanisms underlying pluripotenty and refining the methodology of iPSC generation will have a significant impact on future development of regenerative medicine.

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

Cited by 1,086 publications

References 50 publications

Two-Phase Analysis of Molecular Pathways Underlying Induced Pluripotent Stem Cell Induction

Two-Phase Analysis of Molecular Pathways Underlying Induced Pluripotent Stem Cell Induction

The BRG1 ATPase of chromatin remodeling complexes is involved in modulation of mesenchymal stem cell senescence through RB–P53 pathways

Mechanism and methods to induce pluripotency

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