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 SOX9
Homo sapiens
 HIF1A
Homo sapiens
 Pax6
Mus musculus
 PAX6
Homo sapiens
 Snai2
Mus musculus
 PPARA
Homo sapiens
 Ppara
Mus musculus
 Thrb
Mus musculus
 SNAI2
Homo sapiens
 Tbr1
Mus musculus
Transcription Factor Encyclopedia  BETA
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Overview

The transcription factor Sox2 belongs to the SOX (Sry-related HMG Box) family of proteins. Sox2 is a master regulator that, together with another transcription factor Oct-3/4, controls a crucial and tightly regulated network of genes that orchestrate mammalian embryogenesis[1], [2]. Accordingly, Sox2 is essential for normal mammalian embryogenesis[1]. Recent studies demonstrate that small changes in the levels of Sox2 in embryonic stem (ES) cells trigger their differentiation into multiple cell types[3][1]. It is also essential for early neurogenesis where its expression becomes restricted to the neural plate, and later to neural stem cells[4][5]. Sox2 is one of the four original factors (Sox2, Oct-3/4, Klf4, cMyc) found to reprogram somatic cells to a pluripotent stem cell state[6]. Importantly, the presence of Sox2 in certain cell types, such as melanocytes and neural progenitors, makes them more amenable to somatic cell reprogramming [7][8].

Sox2 belongs to the B1 subgroup of the Sox family of proteins, which also includes highly homologous members, Sox1 and 3[9]. Sox2 recognizes and binds a 7bp long cis element (HMG site) in the minor groove of the DNA. In ES cells, it co-operates with Oct-3/4 and binds an HMG/POU cassette, a composite element consisting of an HMG site and an adjacent POU site (to which Oct-3/4 binds) located within the regulatory regions of their target genes[10][11][12] [13]. This cooperative binding drives the transcription of multiple Sox2:Oct-3/4 target genes (including Sox2 and Oct-3/4 themselves), many of which are essential for embryogenesis. Moreover, recent studies have demonstrated that Sox2 and Oct-3/4, along with members of the polycomb repressive complex (transcriptional repressors) are associated with hundreds of genes in ES cells. This suggests that a vast network of genes is controlled by these master regulators[10][14] in both human and mouse ES cells. In this regard, a comparison of human and mouse Sox2 proteins reveals small differences in their amino acid sequence, but no difference in the functionality of the two proteins has been reported to date. Work from our lab and others utilizing mouse Sox2 have demonstrated that small increases of Sox2 in ES cells inhibit the expression of its target genes, and promote ES cell differentiation[3][12]. These studies argue that Sox2 acts as a molecular rheostat in ES cells, and that its level needs to be tightly controlled in order to maintain pluripotency. In ES cells, transcription of the Sox2 gene is driven largely by an enhancer located downstream of the transcription start site, which contains an HMG/POU cassette [15][16]. Sox2 appears to contain >20 enhancers, which regulate its expression during various stages of neural development[17].

References
  1. Avilion AA et al. Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev., 17(1):126-40. (PMID 12514105)
  2. Nichols J et al. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell, 95(3):379-91. (PMID 9814708)
  3. Kopp JL et al. Small increases in the level of Sox2 trigger the differentiation of mouse embryonic stem cells. Stem Cells, 26(4):903-11. (PMID 18238855)
  4. Zappone MV et al. Sox2 regulatory sequences direct expression of a (beta)-geo transgene to telencephalic neural stem cells and precursors of the mouse embryo, revealing regionalization of gene expression in CNS stem cells. Development, 127(11):2367-82. (PMID 10804179)
  5. Graham V et al. SOX2 functions to maintain neural progenitor identity. Neuron, 39(5):749-65. (PMID 12948443)
  6. Takahashi K and Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4):663-76. (PMID 16904174)
  7. Utikal J et al. Sox2 is dispensable for the reprogramming of melanocytes and melanoma cells into induced pluripotent stem cells. J. Cell. Sci. (PMID 19723802)
  8. Eminli S et al. Reprogramming of neural progenitor cells into induced pluripotent stem cells in the absence of exogenous Sox2 expression. Stem Cells, 26(10):2467-74. (PMID 18635867)
  9. Schepers GE et al. Twenty pairs of sox: extent, homology, and nomenclature of the mouse and human sox transcription factor gene families. Dev. Cell, 3(2):167-70. (PMID 12194848)
  1. Boyer LA et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell, 122(6):947-56. (PMID 16153702)
  2. Loh YH et al. The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat. Genet., 38(4):431-40. (PMID 16518401)
  3. Boer B et al. Elevating the levels of Sox2 in embryonal carcinoma cells and embryonic stem cells inhibits the expression of Sox2:Oct-3/4 target genes. Nucleic Acids Res., 35(6):1773-86. (PMID 17324942)
  4. Chakravarthy H et al. Identification of DPPA4 and other genes as putative Sox2:Oct-3/4 target genes using a combination of in silico analysis and transcription-based assays. J. Cell. Physiol., 216(3):651-62. (PMID 18366076)
  5. Boyer LA et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature, 441(7091):349-53. (PMID 16625203)
  6. Tomioka M et al. Identification of Sox-2 regulatory region which is under the control of Oct-3/4-Sox-2 complex. Nucleic Acids Res., 30(14):3202-13. (PMID 12136102)
  7. Boer B et al. Differential activity of the FGF-4 enhancer in F9 and P19 embryonal carcinoma cells. J. Cell. Physiol., 208(1):97-108. (PMID 16523502)
  8. Uchikawa M et al. Functional analysis of chicken Sox2 enhancers highlights an array of diverse regulatory elements that are conserved in mammals. Dev. Cell, 4(4):509-19. (PMID 12689590)
Figures
FIGURE 1 Sox2:Oct-3/4 target genes
Known transcriptional targets of Sox2 and Oct-3/4. The HMG/POU cassettes to which Sox2 and Oct-3/4 co-operatively bind, are depicted as shown, and are located within the regulatory regions of the Sox2:Oct-3/4 target genes. The transcription start site for each gene is represented by the curved black arrow.
This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.