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Other entities represented in this entry:
HGNC Approved Gene Symbol: POU5F1
Cytogenetic location: 6p21.33 Genomic coordinates (GRCh38): 6:31,164,337-31,170,682 (from NCBI)
Transcription factors containing the POU homeodomain have been shown to be important regulators of tissue-specific gene expression in lymphoid and pituitary differentiation and in early mammalian development. To identify members of the POU family of transcription factors that may be involved in the tissue-specific regulation of expression of genes in insulin-secreting cells of the pancreas, Takeda et al. (1992) used PCR and degenerate oligonucleotide primers specific for the homeodomain to amplify POU-related sequences in human pancreatic islet mRNA. The sequences of 2 of the PCR products were identical to human OCT1 (164175) and 2 others were homologous to mouse Oct3. Takeda et al. (1992) showed that 2 forms of OCT3 mRNA are expressed in adult tissues as a result of alternative splicing--OCT3A and OCT3B. OCT3A and OCT3B are composed of 360 and 265 amino acids, respectively, of which the 225 amino acids at the COOH-termini are identical. The sequence of human OCT3A showed 87% amino acid identity with mouse Oct3. Reverse transcriptase PCR showed low level of expression in both OCT3A and OCT3B mRNA in all adult human tissues examined.
Niwa et al. (2000) used conditional expression and repression in murine embryonic stem (ES) cells to determine requirements for Oct3/4 in the maintenance of developmental potency. Although transcriptional determination has usually been considered as a binary on-off control system, they found that the precise level of Oct3/4 governs 3 distinct fates of ES cells. A less-than-2-fold increase in expression causes differentiation into primitive endoderm and mesoderm. In contrast, repression of Oct3/4 induces loss of pluripotency and dedifferentiation to trophectoderm. Thus, a critical amount of Oct3/4 is required to sustain stem cell self-renewal, and up- or downregulation induces divergent developmental programs. Niwa et al. (2000) suggested that their findings established a role for Oct3/4 as a master regulator of pluripotency that controls lineage commitment and illustrated the sophistication of critical transcriptional regulators and the consequent importance of quantitative analyses.
Guo et al. (2002) showed that mammalian Foxd3 (611539) and Oct4 bound identical regulatory DNA sequences in the osteopontin (SPP1; 166490) promoter. Oct4 interacted directly with Foxd3, and both proteins activated the osteopontin promoter, either alone or in combination. Foxd3 also activated the Foxa1 (602294) and Foxa2 (600288) promoters, and coexpression of Oct4 inhibited Foxd3-mediated activation of these promoters.
Using affinity chromatography, Xu et al. (2004) showed that mouse Wwp2 (602308), an E3 ubiquitin ligase, interacted with Oct4. Mutation analysis showed that the WW domains of Wwp2 were required for the interaction, and both the N- and C-terminal regions of Oct4 could interact with Wwp2. Wwp2 ubiquitinated Oct4 in vitro and in vivo, and this activity required the catalytic cysteine within the HECT domain of Wwp2. Ubiquitination of Oct4 inhibited its transcriptional activity and directed its degradation by the proteasome. Expression of both Wwp2 and Oct4 was reduced with differentiation in mouse embryonic stem cells.
Zeineddine et al. (2006) showed that Oct3 has a role in cardiac development in the early mouse embryo.
Wang et al. (2006) explored the protein network in which Nanog (607937) operates in mouse ES stem cells. Using affinity purification of Nanog under native conditions followed by mass spectrometry, Wang et al. (2006) identified physically associated proteins. In an iterative fashion they also identified partners of several Nanog-associated proteins (including Oct4), validated the functional relevance of selected newly identified components, and constructed a protein interaction network. The network is highly enriched for nuclear factors that are individually critical for maintenance of the ES cell state and coregulated on differentiation. The network is linked to multiple corepressor pathways and is composed of numerous proteins whose encoding genes are putative direct transcriptional targets of its members. Wang et al. (2006) concluded that this tight protein network seems to function as a cellular module dedicated to pluripotency.
Induced pluripotent stem (iPS) cells can be generated from mouse fibroblasts by retrovirus-mediated introduction of 4 transcription factors, Oct3/4, Sox2 (184429), c-Myc (190080), and Klf4 (602253), and subsequent selection for Fbx15 (609093) expression (Takahashi and Yamanaka, 2006). These iPS cells, hereafter called Fbx15 iPS cells, are similar to embryonic stem (ES) cells in morphology, proliferation, and teratoma formation; however, they are different with regard to gene expression and DNA methylation patterns, and fail to produce adult chimeras. Okita et al. (2007) showed that selection for Nanog expression results in germline-competent iPS cells with increased ES cell-like gene expression and DNA methylation patterns compared with Fbx15 iPS cells. The 4 transgenes were strongly silenced in Nanog iPS cells.
Wernig et al. (2007) independently demonstrated that the transcription factors Oct4, Sox2, c-Myc, and Klf4 can induce epigenetic reprogramming of a somatic genome to an embryonic pluripotent state. In contrast to selection for Fbx15 activation (Takahashi and Yamanaka, 2006), fibroblasts that had reactivated the endogenous Oct4 (Oct4-neo) or Nanog (Nanog-neo) loci grew independently of feeder cells, expressed normal Oct4, Nanog, and Sox2 RNA and protein levels, were epigenetically identical to ES cells by a number of criteria, and were able to generate viable chimeras, contribute to the germline, and generate viable late-gestation embryos after injection into tetraploid blastocysts. Transduction of the 4 factors generated significantly more drug-resistant cells from Nanog-neo than from Oct4-neo fibroblasts, but a higher fraction of Oct4-selected cells had all the characteristics of pluripotent ES cells, suggesting that Nanog activation is a less stringent criterion for pluripotency than Oct4 activation.
Using Oct4, Sox2, Klf4, and Myc, Park et al. (2008) derived iPS cells from fetal, neonatal, and adult human primary cells, including dermal fibroblasts isolated from a skin biopsy of a healthy research subject. Human iPS cells resemble embryonic stem cells in morphology and gene expression and in the capacity to form teratomas in immune-deficient mice. Park et al. (2008) concluded that defined factors can reprogram human cells to pluripotency, and they established a method whereby patient-specific cells might be established in culture.
Yu et al. (2007) showed that 4 factors, OCT4, SOX2 (184429), NANOG (607937), and LIN28 (611043), are sufficient to reprogram human somatic cells to pluripotent stem cells that exhibit the essential characteristics of embryonic stem cells. These induced pluripotent human stem cells have normal karyotypes, express telomerase activity, express cell surface markers and genes that characterize human ES cells, and maintain the developmental potential to differentiate into advanced derivatives of all 3 primary germ layers.
Kim et al. (2008) showed that adult mouse neural stem cells express higher endogenous levels of Sox2 and c-Myc than embryonic stem cells and that exogenous Oct4 together with either Klf4 or c-Myc is sufficient to generate iPS cells from neural stem cells. These 2-factor iPS cells are similar to embryonic stem cells at the molecular level, contribute to development of the germ line, and form chimeras. Kim et al. (2008) proposed that, in inducing pluripotency, the number of reprogramming factors can be reduced when using somatic cells that endogenously express appropriate levels of complementing factors.
Stadtfeld et al. (2008) generated mouse iPS cells from fibroblasts and liver cells by using nonintegrating adenoviruses transiently expressing Oct4, Sox2, Klf4, and c-Myc. These adenoviral iPS cells showed DNA demethylation characteristic of reprogrammed cells, expressed endogenous pluripotency genes, formed teratomas, and contributed to multiple tissues, including the germ cell line, in chimeric mice. Stadtfeld et al. (2008) concluded that their results provided strong evidence that insertional mutagenesis is not required for in vitro reprogramming.
Okita et al. (2008) independently reported the generation of mouse iPS cells without viral vectors. Repeated transfection of 2 expression plasmids, one containing the cDNAs of Oct3/4, Sox2, and Klf4 and the other containing the c-Myc cDNA, into mouse embryonic fibroblasts resulted in iPS cells without evidence of plasmid integration, which produced teratomas when transplanted into mice and contributed to adult chimeras. Okita et al. (2008) concluded that the production of virus-free iPS cells, albeit from embryonic fibroblasts, addresses a critical safety concern for potential use of iPS cells in regenerative medicine.
Donohoe et al. (2009) demonstrated that OCT4 lies at the top of the X chromosome inactivation (XCI) hierarchy, and regulates XCI by triggering X chromosome pairing and counting. OCT4 directly binds TSIX (300181) and XITE (300074), 2 regulatory noncoding RNA genes of the X inactivation center, and also complexes with SCI transfactors CTCF (604167) and YY1 (600013) through protein-protein interactions. Depletion of Oct4 in female mouse embryonic stem cells blocked homologous X-chromosome pairing and resulted in the inactivation of both X chromosomes. Donohoe et al. (2009) concluded that they identified the first trans-factor that regulates counting, and ascribed new functions to OCT4 during X chromosome reprogramming.
Kim et al. (2009) showed that Oct4 alone is sufficient to directly reprogram adult mouse neural stem cells to iPS cells. Kim et al. (2009) then showed that OCT4 alone could convert human fetal neural stem cells into induced pluripotent stem (iPS) cells.
Hanna et al. (2009) demonstrated that the reprogramming by Oct4, Sox2, Klf4, and Myc transcription factors is a continuous stochastic process where almost all mouse donor cells eventually give rise to iPS cells on continued growth and transcription factor expression. Additional inhibition of the p53 (191170)/p21 (116899) pathway or overexpression of Lin28 increased the cell division rate and resulted in an accelerated kinetics of iPS cell formation that was directly proportional to the increase in cell proliferation. In contrast, Nanog (607937) overexpression accelerated reprogramming in a predominantly cell division rate-independent manner. Quantitative analyses defined distinct cell division rate-dependent and -independent modes for accelerating the stochastic course of reprogramming, and suggested that the number of cell divisions is a key parameter driving epigenetic reprogramming to pluripotency.
Using chromatin immunoprecipitation analysis, Yu et al. (2009) showed that mouse Zfp206 (ZSCAN10; 618365)and Oct4 reciprocally regulated expression of one another in ES cells through promoter binding. Genomewide mapping of Zfp206 targets in mouse ES cells identified Zfp206, Oct4, and Sox2 as key components of a large transcriptional regulatory network. Zfp206 selectively activated or repressed transcription of its target genes by binding to their promoters in ES cells. Many of these same genes were also regulated by Oct4 and Sox2, which colocalized and physically interacted with Zfp206 in a macromolecular complex.
The generation of iPS cells is asynchronous and slow, the frequency is low (less than 0.1%), and DNA demethylation constitutes a bottleneck. To determine regulatory mechanisms involved in reprogramming, Bhutani et al. (2010) generated interspecies heterokaryons (fused mouse ES cells and human fibroblasts) that induced reprogramming synchronously, frequently, and fast. Bhutani et al. (2010) showed that reprogramming toward pluripotency in single heterokaryons was initiated without cell division or DNA replication, rapidly (1 day) and efficiently (70%). Short interfering RNA-mediated knockdown showed that AID (605257) is required for promoter demethylation and induction of OCT4 and NANOG gene expression. AID protein bound silent methylated OCT4 and Nanog promoters in fibroblasts, but not active demethylated promoters in ES cells. Bhutani et al. (2010) concluded that their data provided the first evidence that mammalian AID is required for active DNA demethylation and initiation of nuclear reprogramming toward pluripotency in human somatic cells.
Using chromatin immunoprecipitation sequencing (ChIP-Seq), Kunarso et al. (2010) showed that genomic regions bound by CTCF were highly conserved between undifferentiated mouse and human embryonic stem cells. However, very little conservation was found for regions bound by OCT4 and NANOG. Most of the differences in OCT4 and NANOG binding between species appeared to be due to species-specific insertion of transposable elements, such as endogenous ERV1 repeats, that generated unique OCT4- and NANOG-repeat-associated binding sites.
Chia et al. (2010) reported a genomewide RNA interference screen to identify genes that regulate self-renewal and pluripotency properties in human embryonic stem cells. Functionally distinct complexes involved in transcriptional regulation and chromatin remodeling were among the factors identified in the screen. To understand the roles of these potential regulators of human embryonic stem cells, Chia et al. (2010) studied transcription factor PRDM14 (611781) to gain insights into its functional roles in the regulation of pluripotency. Chia et al. (2010) showed that PRDM14 regulates directly the expression of key pluripotency gene POU5F1 through its proximal enhancer. Genomewide location profiling experiments revealed that PRDM14 colocalized extensively with other key transcription factors such as OCT4, NANOG, and SOX2 (184429), indicating that PRDM14 is integrated into the core transcriptional regulatory network. More importantly, in a gain-of-function assay, they showed that PRDM14 is able to enhance the efficiency of reprogramming of human fibroblasts in conjunction with OCT4, SOX2, and KLF4 (602253).
Rais et al. (2013) showed that depleting MBD3 (603573), a core member of the MBD3/NURD (nucleosome remodeling and deacetylation) repressor complex, together with OSKM (OCT4, SOX2, KLF4, and MYC) transduction and reprogramming in naive pluripotency-promoting conditions, result in deterministic and synchronized iPS cell reprogramming (nearly 100% efficiency within 7 days from mouse and human cells). Rais et al. (2013) stated that their findings uncovered a dichotomous molecular function for the reprogramming factors, serving to reactivate endogenous pluripotency networks while simultaneously directly recruiting the MBD3/NURD repressor complex that potently restrains the reactivation of OSKM downstream target genes. Subsequently, the latter interactions, which are largely depleted during early preimplantation development in vivo, lead to a stochastic and protracted reprogramming trajectory toward pluripotency in vitro. Rais et al. (2013) concluded that their deterministic reprogramming approach offered a novel platform for the dissection of molecular dynamics leading to establishing pluripotency at unprecedented flexibility and resolution.
After fertilization, maternal factors direct development and trigger zygotic genome activation (ZGA) at the maternal-to-zygotic transition. In zebrafish, ZGA is required for gastrulation and clearance of maternal mRNAs, which is in part regulated by the conserved microRNA miR430 (homologous to human MIR302A, 614596). Lee et al. (2013) showed that Nanog (607937), Pou5f1 (164177), and SoxB1 regulate zygotic gene activation in zebrafish. Lee et al. (2013) identified several hundred genes directly activated by maternal factors, constituting the first wave of zygotic transcription. Ribosome profiling revealed that Nanog, Sox19B (a member of the SoxB1 family), and Pou5f1 are the most highly translated transcription factors prior to maternal-to-zygotic transition. Combined loss of these factors resulted in developmental arrest before gastrulation and a failure to activate greater than 75% of zygotic genes, including miR430. Lee et al. (2013) concluded that maternal Nanog, Pou5f1, and SoxB1 are required to initiate the zygotic developmental program and induce clearance of the maternal program by activating miR430 expression.
De Wit et al. (2013) combined chromatin conformation capture technologies with chromatin factor binding data to demonstrate that inactive chromatin is unusually disorganized in pluripotent stem cell nuclei. They showed that gene promoters engage in contacts between topologic domains in a largely tissue-independent manner, whereas enhancers have a more tissue-restricted interaction profile. Notably, genomic clusters of pluripotency factor binding sites find each other very efficiently, in a manner that is strictly pluripotent stem cell-specific, dependent on the presence of Oct4 and Nanog proteins, and inducible after artificial recruitment of Nanog to a selected chromosomal site. De Wit et al. (2013) concluded that pluripotent stem cells have a unique higher-order genome structure shaped by pluripotency factors, and speculated that this interactome enhances the robustness of the pluripotent state.
Leichsenring et al. (2013) found that zebrafish Pou5f1, a homolog of the mammalian pluripotency transcription factor Oct4, occupies SOX-POU binding sites before the onset of zygotic transcription and activates the earliest zygotic genes. Leichsenring et al. (2013) concluded that their data positioned Pou5f1 and SOX-POU sites at the center of the zygotic gene activation network of vertebrates and provided a link between zygotic gene activation and pluripotency control.
By knockdown and overexpression analyses, Jung et al. (2013) showed that AGO2 (606229) enhanced stemness-related gene expression and proliferation of human adipose tissue-derived stem cells (hATSCs). RT-PCR analysis revealed that AGO2 regulated expression of itself and growth-associated genes, including OCT4, by binding their promoter regions. Chromatin immunoprecipitation analysis revealed that OCT4 targeted the MBD6 gene (619458) and directly controlled its expression and MBD6-mediated proliferation of hATSCs. MBD6 regulated functional gene clusters at the protein level in hATSCs, thereby inhibiting their mesodermal differentiation and controlling their stemness and differentiation.
Fogarty et al. (2017) used CRISPR-Cas9-mediated genome editing to investigate the function of the pluripotency transcription factor OCT4 during human embryogenesis. They specifically targeted the gene encoding OCT4 in diploid human zygotes and found that blastocyst development was compromised. Transcriptomics analysis revealed that, in OCT4-null cells, gene expression was downregulated not only for extra-embryonic trophectoderm genes, such as CDX2 (600297), but also for regulators of the pluripotent epiblast, including NANOG (607937). By contrast, Oct4-null mouse embryos maintained the expression of orthologous genes, and blastocyst development was established, but maintenance was compromised.
Malakootian et al. (2017) found that exogenous expression of the long noncoding RNA PSORS1C3 (618690) led to upregulation of the OCT4 B1 variant in HEK293T cells.
Mirzadeh Azad et al. (2019) found that PSORS1C3, which overlaps the OCT4 gene, had 2 endogenously active promoters, designated P0 and P1, that initiated transcription of long and short variants, respectively. Reporter assays showed that P0 was responsive to activation of glucocorticoid receptor (NR3C1; 138040) by dexamethasone (DEX), resulting in upregulation of PSORS1C3 short variants and OCT4 isoforms and downregulation of PSORS1C3 long variants. Furthermore, P0 also functioned as an enhancer for OCT4, as deletion of the glucocorticoid response element (GRE) in P0 significantly decreased expression of OCT4 isoforms in human A549 lung cancer cells. However, activation by DEX caused elevated expression of PSORS1C3 short variants and OCT4 isoforms in GRE-deleted cells.
Takeda et al. (1992) showed that the OCT3 gene spans about 7 kb and consists of 5 exons.
Using pairs of sequence-specific primers and DNA from a panel of somatic cell hybrids, Takeda et al. (1992) mapped the OCT3 gene to chromosome 6. This localization was confirmed by linkage of a RFLP in 9 CEPH families, indicating tight linkage to HLA-A, -B, -C, and -DR. No recombinants were identified with any of these and lod scores ranged from 5.72 to 10.84. By in situ hybridization, Guillaudeux et al. (1993) mapped the OTF3 gene to 6p22-p21.3 within or close to the human MHC class I region. The homologous mouse gene, Otf3, is located on mouse chromosome 17 between the Q and T regions of the major histocompatibility complex. Takeda et al. (1992) identified a related gene, symbolized OTF3C (OTF3P1), which is a retroposon located on human chromosome 8; this gene is a pseudogene. Guillaudeux et al. (1993) localized one OTF3-like copy (OTF3L) to 12p13 by in situ hybridization. The functional significance of this gene was not known. Using recombinant families, pulsed field gel electrophoresis, and YAC mapping, Crouau-Roy et al. (1994) localized the OTF3 gene within the MHC class I region, approximately 100 kb telomeric to the HLA-C gene.
POU5F1/EWS Fusion Gene
Yamaguchi et al. (2005) identified a t(6;22)(p21;q12) translocation in tumor tissue derived from an undifferentiated sarcoma from the pelvic bone of a 39-year-old woman. The translocation resulted in a POU5F1/EWS (EWSR1; 133450) chimeric gene composed of the N-terminal domain of EWS that functions as a transcriptional activation domain and the C-terminal DNA-binding domain of POU5F1. Yamaguchi et al. (2005) suggested that the tumor may be a variant of Ewing sarcoma (612219).
Via homologous recombination in ES cells, Nichols et al. (1998) generated mice with targeted disruption of the Oct4, or Oct3, gene. Oct4-deficient embryos developed to the blastocyst stage, but the inner cell mass cells were not pluripotent. Instead, they were restricted to differentiation along the extraembryonic trophoblast lineage. Furthermore, in the absence of a true inner cell mass, trophoblast proliferation was not maintained in Oct4 -/- embryos. Expansion of trophoblast precursors was restored, however, by an Oct4 target gene product, fibroblast growth factor-4 (see 164980). Therefore, Oct4 also determines paracrine growth factor signaling from stem cells to the trophectoderm. Nichols et al. (1998) concluded that the activity of Oct4 is essential for the identity of the pluripotential founder cell population in the mammalian embryo.
Tay et al. (2008) demonstrated the existence of many naturally occurring miRNA targets in the amino acid coding sequences of the mouse Nanog (607937), Oct4, and Sox2 (184429) genes. Some of the mouse targets analyzed do not contain the miRNA seed, whereas others span exon-exon junctions or are not conserved in the human and rhesus genomes. MiRNA134 (610164), miRNA296 (610945), and miRNA470, upregulated on retinoic acid-induced differentiation of mouse embryonic stem cells, target the coding sequence of each transcription factor in various combinations, leading to transcriptional and morphologic changes characteristic of differentiating mouse embryonic stem cells, and resulting in a new phenotype. Silent mutations at the predicted targets abolished miRNA activity, prevented the downregulation of the corresponding genes, and delayed the induced phenotype. Tay et al. (2008) concluded that their findings demonstrated the abundance of coding sequence-located miRNA targets, some of which can be species-specific, and supported an augmented model whereby animal miRNAs exercise their control on mRNAs through targets that can reside beyond the 3-prime untranslated region.
Oct3 is present in mouse oocytes before and after fertilization. Rosner et al. (1991) reported that when fertilized oocytes were injected with antisense Oct3 oligonucleotides or double-stranded DNA containing the octamer motif, embryonic DNA synthesis was inhibited and the embryos were arrested at the 1-cell stage. In vitro synthesized Oct3 mRNA rescued the developmental block induced by antisense Oct3 oligonucleotide. Thus, maternally inherited Oct3 appeared to be required for DNA replication and division of the 1-cell embryo. However, the authors published a retraction: 'Recent investigations have revealed that the experimental evidence supporting the conclusions of the paper by Rosner et al. (Cell 64, 1103-1110, 1991) has been fabricated by one of the authors (M.R.) without any knowledge by the others. We therefore retract this paper in its entirety.' This seems to be scientific fraud comparable to that perpetrated by the infamous John R. Darsee, who confessed to fabrication of data showing linkage of HLA and familial hypertrophic cardiomyopathy (192600).
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