Oct-4

Oct-4 (octamer-binding is_associated_with::transcription factor 4) also known as POU5F1 (POU domain, class 5, transcription factor 1) is a is_associated_with::protein that in humans is encoded by the POU5F1 is_associated_with::gene. Oct-4 is a homeodomain transcription factor of the is_associated_with::POU family. This protein is critically involved in the self-renewal of undifferentiated embryonic is_associated_with::stem cells. As such, it is frequently used as a marker for undifferentiated cells. Oct-4 expression must be closely regulated; too much or too little will cause differentiation of the cells.

The octamer (made of eight units) in this family of transcription factors is the DNA is_associated_with::nucleotide sequence "ATTTGCAT", the etymology for the naming of the is_associated_with::octamer transcription factor.

Expression and function
Oct-4 transcription factor is initially active as a maternal factor in the oocyte but remains active in embryos throughout the preimplantation period. Oct-4 expression is associated with an undifferentiated phenotype and tumors. Gene knockdown of Oct-4 promotes differentiation, thereby demonstrating a role for these factors in human embryonic stem cell self-renewal. Oct-4 can form a heterodimer with is_associated_with::Sox2, so that these two proteins bind DNA together.

Mouse embryos that are Oct-4-deficient or have low expression levels of Oct-4 fail to form the inner cell mass, lose pluripotency and differentiate into trophectoderm. Therefore, the level of Oct-4 expression in mice is vital for regulating pluripotency and early cell differentiation since one of its main functions is to keep the embryo from differentiating.

Orthologs
Orthologs of Oct-4 exist in humans and several other species including:

Structural Information
Oct-4 contains the following is_associated_with::protein domains:

Implications in disease
Oct-4 has been implicated in tumorigenesis of adult germ cells. is_associated_with::Ectopic expression of the factor in adult mice has been found to cause the formation of is_associated_with::dysplastic lesions of the skin and intestine. The intestinal dysplasia resulted from an increase in progenitor cell population and the upregulation of β-catenin transcription through the inhibition of cellular differentiation.

Animal model
In 2000, Niwa et al. used conditional expression and repression in murine embryonic stem (ES) cells to determine requirements for Oct-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 Oct-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 Oct-4 induces loss of pluripotency and dedifferentiation to trophectoderm. Thus, a critical amount of Oct-4 is required to sustain stem cell self-renewal, and up- or down regulation induces divergent developmental programs. Niwa et al. suggested that their findings established a role for Oct-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 analyzes.

The transcription factors Oct-4, Sox2 and Nanog are capable of inducing the expression of each other, and are essential for maintaining the self-renewing undifferentiated state of the is_associated_with::inner cell mass of the blastocyst, as well as in is_associated_with::embryonic stem cells (which are cell lines derived from the inner cell mass).

Oct-4 is one of the transcription factors used to create is_associated_with::induced pluripotent stem cells, together with is_associated_with::Sox2, Klf4 and often c-is_associated_with::Myc in mouse,   demonstrating its capacity to induce an embryonic stem cell-like state. It was later deterimined that only two of these four factors, Oct4 and Klf4 were sufficient to reprogram mouse adult neural stem cells. Finally it was shown that a single factor, Oct-4 was sufficient for this transformation.

In embryonic stem cells
In in-vitro experiments of murine Embryonic Stem Cells, Oct-4 has often been used as a marker of stemness, as differentiated cells show reduced expression of this marker.

Oct3/4 can both repress and activate the is_associated_with::Rex1 promoter. In cells that already express high level of Oct3/4, exogenously transfected Oct3/4 will lead to the repression of Rex1. However, in cells that are not actively expressing Oct3/4, an exogenous transfection of Oct3/4 will lead to the activation of Rex1. This implies a dual regulatory ability of Oct3/4 on Rex1. At low levels of the Oct3/4 protein, the Rex1 promoter is activated, while at high levels of the Oct3/4 protein, the Rex1 promoter is repressed.

In adult stem cells
Several studies suggest a role for Oct-4 in sustaining self-renewal capacity of adult somatic stem cells (i.e. stem cells from epithelium, bone marrow, liver, etc.). Other scientists have produced evidence to the contrary, and dismiss those studies as artifacts of in vitro culture, or interpreting background noise as signal, and warn about Oct-4 is_associated_with::pseudogenes giving false detection of Oct-4 expression. Oct-4 has also been implicated as a marker of is_associated_with::cancer stem cells.