Sox2 acts as a transcriptional repressor in neural stem cells

BMC Neuroscience

Paul J Scotting²  Sally P Wheatley²  Paul E Goodwin²  Jamie RM Webster²  Jaime Hughes²  Carolina A Novoa³  Zulfiqar A Laghari¹  Yu-Ru Liu² 

[1] Department of Physiology, University of Sindh, Jamshoro, Pakistan;Centre for Genetics and Genomics, School of Life Sciences, Queen’s Medical Centre, Nottingham NG7 2UH, England;BCCRC, 675 West 10th Avenue, Vancouver, BC, Canada

关键词: Neural stem cells;    Repressor;    Grg;    Groucho;    Sox2;   

Others  :  1091468
DOI  :  10.1186/1471-2202-15-95

 received in 2014-05-20, accepted in 2014-07-30,  发布年份 2014

【 摘 要 】

Background

The transcription factor, Sox2, is central to the behaviour of neural stem cells. It is also one of the key embryonic stem cell factors that, when overexpressed can convert somatic cells into induced pluripotent cells. Although generally studied as a transcriptional activator, recent evidence suggests that it might also repress gene expression.

Results

We show that in neural stem cells Sox2 represses as many genes as it activates. We found that Sox2 interacts directly with members of the groucho family of corepressors and that repression of several target genes required this interaction. Strikingly, where many of the genes activated by Sox2 encode transcriptional regulators, no such genes were repressed. Finally, we found that a mutant form of Sox2 that was unable to bind groucho was no longer able to inhibit differentiation of neural stem cells to the same extent as the wild type protein.

Conclusions

These data reveal a major new mechanism of action for this key transcription factor. In the context of our understanding of endogenous stem cells, this highlights the need to determine how such a central regulator can distinguish which genes to activate and which to repress.

【 授权许可】

   
2014 Liu et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Yamanaka S, Blau HM: Nuclear reprogramming to a pluripotent state by three approaches. Nature 2010, 465:704-712.
• [2]Hanna JH, Saha K, Jaenisch R: Pluripotency and cellular reprogramming: facts, hypotheses, unresolved issues. Cell 2010, 143:508-525.
• [3]Graham V, Khudyakov J, Ellis P, Pevny L: SOX2 Functions to Maintain Neural Progenitor. Identity 2003, 39:749-765.
• [4]Rex M, Orme A, Uwanogho D, Tointon K, Wigmore PM, Sharpe PT, Scotting PJ: Dynamic expression of chicken Sox2 and Sox3 genes in ectoderm induced to form neural tissue. Dev Dyn 1997, 209:323-332.
• [5]Pevny LH, Nicolis SK: Sox2 roles in neural stem cells. Int J Biochem Cell Biol 2009, 42:421-424.
• [6]Masui S, Nakatake Y, Toyooka Y, Shimosato D, Yagi R, Takahashi K, Okochi H, Okuda A, Matoba R, Sharov A, Ko MSH, Niwa H: Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells. Nat Cell Biol 2007, 9:625-635.
• [7]Greber B, Lehrach H, Adjaye J: Silencing of core transcription factors in human EC cells highlights the importance of autocrine FGF signaling for self-renewal. BMC Dev Biol 2007, 7:46.
• [8]Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS, Zucker JP, Guenther MG, Kumar RM, Murray HL, Jenner RG, Gifford DK, Melton DA, Jaenisch R, Young RA: Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 2005, 122:947-956.
• [9]Chen X, Xu H, Yuan P, Fang F, Huss M, Vega VB, Wong E, Orlov YL, Zhang W, Jiang J, Loh Y-H, Yeo HC, Yeo ZX, Narang V, Govindarajan KR, Leong B, Shahab A, Ruan Y, Bourque G, Sung W-K, Clarke ND, Wei C-L, Ng HH: Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 2008, 133:1106-1117.
• [10]Kim J, Chu J, Shen X, Wang J, Orkin SH: An extended transcriptional network for pluripotency of embryonic stem cells. Cell 2008, 132:1049-1061.
• [11]Sharov AA, Masui S, Sharova LV, Piao Y, Aiba K, Matoba R, Xin L, Niwa H, Ko MS: Identification of Pou5f1, Sox2, and Nanog downstream target genes with statistical confidence by applying a novel algorithm to time course microarray and genome-wide chromatin immunoprecipitation data. BMC Genomics 2008, 9:269.
• [12]Brantjes H, Barker N, van Es J, Clevers H: TCF: Lady Justice casting the final verdict on the outcome of Wnt signalling. Biol Chem 2002, 383:255-261.
• [13]Eden E, Navon R, Steinfeld I, Lipson D, Yakhini Z: GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics 2009, 10:48.
• [14]Brantjes H, Roose J, van De Wetering M, Clevers H: All Tcf HMG box transcription factors interact with Groucho-related co-repressors. Nucleic Acids Res 2001, 29:1410-1419.
• [15]Cavallo RA, Cox RT, Moline MM, Roose J, Polevoy GA, Clevers H, Peifer M, Bejsovec A: Drosophila Tcf and Groucho interact to repress Wingless signalling activity. Nature 1998, 395:604-608.
• [16]Shi W, Wang H, Pan G, Geng Y, Guo Y, Pei D: Regulation of the pluripotency marker Rex-1 by Nanog and Sox2. J Biol Chem 2006, 281:23319-23325.
• [17]Cavallaro M, Mariani J, Lancini C, Latorre E, Caccia R, Gullo F, Valotta M, DeBiasi S, Spinardi L, Ronchi A, Wanke E, Brunelli S, Favaro R, Ottolenghi S, Nicolis SK: Impaired generation of mature neurons by neural stem cells from hypomorphic Sox2 mutants. Development 2008, 135(3):541-557.
• [18]Bylund M, Andersson E, Novitch BG, Muhr J: Vertebrate neurogenesis is counteracted by Sox1-3 activity. Nat Neurosci 2003, 6:1162-1168.
• [19]Graham V, Khudyakov J, Ellis P, Pevny L: SOX2 functions to maintain neural progenitor identity. Neuron 2003, 39:749-765.
• [20]Goldstein RE, Cook O, Dinur T, Pisante A, Karandikar UC, Bidwai A, Paroush Z: An eh1-like motif in odd-skipped mediates recruitment of Groucho and repression in vivo. Mol Cell Biol 2005, 25:10711-10720.
• [21]Yaklichkin S, Vekker A, Stayrook S, Lewis M, Kessler DS: Prevalence of the EH1 Groucho interaction motif in the metazoan Fox family of transcriptional regulators. BMC Genomics 2007, 8:201.
• [22]Shih Y, Kuo C, Hirst C, Dee C, Liu Y, Laghari Z, Scotting PJ: SoxB1 transcription factors restrict organizer gene expression by repressing multiple events downstream of Wnt signalling. Development 2010, 137:2671-2681.
• [23]Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U, Speed TP: Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 2003, 4:249-264.
• [24]Pfaffl MW: A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 2001, 29(9):e45.