SOX2 (Gene SOX2)
SOX2 is an intronless gene that lies within an intron of a gene called SOX2 overlapping transcript (SOX2OT). The SOX2 gene (map locus 3q26.3-q27) product, SRY (sex determining region Y)-box 2, is a 317 amino acids long (34.3 kDa), high mobility group (HMG) domain containing transcription factor that controls totipotent and pluripotent cell status. HMG box domains preferentially bind to distorted DNA without sequence specificity and may bend DNA. SOX2 post-translation sumoylation inhibits binding to many target gene promoter sites.
SOX2, SRY (sex determining region Y)-box 2 and POU5F1/OCT4, another transcription factor, form trimeric complexes within the promoter regions of genes that regulate downstream embryonic development and pluripotency. The Sox2:Oct4 complex is at the top of the regulatory hierarchy of the pluripotent genetic regulatory network, Rodda DJ, et al. (2005). SOX2 coexpresses with OCT4 starting very early in embryogenesis, beginning at the early morula-stage. These factors are found within the inner cell mass (ICM) of the blastocyst of the pre-implantation embryo. Expression of both factors persists within the epiblast, the tissue that differentiates into the embryo and germ cells after blastocyst implantation. SOX2 and OCT4 are also expressed in Embryonic Stem Cells (ES) which are typically, but not always, derived from the ICM of blastocysts. The importance of SOX2 and OCT4 as regulators of pluripotency has been dramatically illustrated by the demonstration that these factors together with c-Myc and Klf4 or Nanog and LIN28 can induce the dedifferentiation of somatic cells into induced pluripotent stem cells (iPS) with many of the features of embryonic stem cells, Takahashi, K. and Yamanaka, S. (2006); Wernig, M. et al. (2007) and Yu, J. et al. (2007). The successful replacement of embryonic stem cells with induced pluripotent stem cells for scientific research and as candidates for clinical therapies will require an extensive knowledge of the roles played by SOX2 and OCT4 as gate-keepers of toti- and pluripotency.
SOX2 and OCT4 bind DNA through their HMG and POU domains, respectively. These DNA binding regions within target gene promoters are frequently closely linked with separations of 0 to 3 nucleotides. SOX2 and OCT4 regulate the expression of each other which is essential for stabilization of pluripotency within cells, such as ES cells, Masui S, et al. (2007). SOX2 and OCT 4 regulate the expression of Nanog, a transcription factor that co-occupies many of the same genes promoters, Rodda DJ, et al. (2005). Nanog is also a very important early regulator of pluripotency. Together SOX2, OCT4 and Nanog co-regulate a growing list of downstream target genes. Target genes include YES1, FGF4, UTF1, Fbx15, Zic3 and ZFP206, but this is only a sampling of the hundreds of genes that are involved. The targets of SOX2, OCT4 and Nanog have recently been identified using time course microarray and genome-wide immunoprecipition data, Sharov, A.A, et al. (2008).
Loss of function SOX2 mutations have been linked to the rare disease microphthalmia syndrome type 3, small eye, (MCOPS3), Ragge NK, et al. (2005); Verma, A.S, and Fitzpatrick, D.R. (2007.)
Sigma offers antibodies, shRNAs and other products useful for the study of the SOX2 Gene.
References:
Masui S, et al. (2007) Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells. Nat Cell Biol. 9: 625-635.
Ragge NK, et al. (2005) SOX2 anophthalmia syndrome. Am J Med Genet A. 135: 1-7; discussion 8.
Rodda DJ, et al. (2005) Transcriptional regulation of nanog by OCT4 and SOX2. J Biol Chem. 280: 24731-24737.
Sharov AA, Masui S, Sharova LV, Piao Y, Aiba K, Matoba R, Xin L, Niwa H, Ko MS. (2008) 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. Genomics. 9: 269. Published on-line.
Takahashi, K. and Yamanaka, S. (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126: 663-676.
Verma AS and Fitzpatrick DR. (2007) Anophthalmia and microphthalmia. Orphanet J Rare Dis. 2: 47.
Wernig, M, et al. (2007) In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448: 318-324.
Yu, J. et al. (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318: 1917-1920.
Footnote: Gene Data Sources: HGNC, Entrez Gene, UniProt/Swiss-Prot, UniProt/TrEMBL, GDB, OMIM, GeneLoc, Ensembl.
|
