Sox2 and Oct-3/4: a versatile pair of master regulators that orchestrate the self-renewal and pluripotency of embryonic stem cells

Abstract

During the past 10 years, remarkable progress has been made in understanding the transcriptional mechanisms that control the biology of stem cells. Given the importance of stem cells in development, regenerative medicine, and cancer, it is no surprise that the pace of discovery continues to accelerate--paradigm-shifting models proposed only a few years ago are quickly giving way to even more sophisticated models of regulation. This review summarizes some of the major advances made in delineating the roles of two transcription factors, Sox2 and Oct-3/4, in stem cell biology. Additionally, unanswered questions related to their mechanisms of action are discussed. When viewed together, it is evident that Sox2 and Oct-3/4 exhibit the major properties expected of master regulators. They are each essential for mammalian development, they help regulate the transcription of other genes that are essential for development, and they influence their own transcription by both positive and negative feedback loops. Moreover, small changes in the levels of either Sox2 or Oct-3/4 trigger the differentiation of embryonic stem (ES) cells. Thus, each functions as a molecular rheostat to control the self-renewal and pluripotency of ES cells. Overall, understanding how Sox2 and Oct-3/4 function mechanistically will not only provide important insights into stem cells in general, but should also have a significant impact on our understanding of induced pluripotent stem (iPS) cells and, hence, the emerging field of regenerative medicine.

Keywords: ES cells; Oct-3/4; Sox2; iPS cells; molecular rheostat; pluripotency; regenerative medicine; stem cells.

Figure 1

Sox2:Oct-3/4 partnership. Sox2 and Oct-3/4 work together cooperatively to regulate their own transcription and the transcription of a large set of downstream target genes in EC and ES cells.

Figure 2

Consensus sequence for HMG/POU Cassettes. A consensus sequence for HMG/POU cassettes derived by comparing the HMG/POU sequences of six Oct-3/4:Sox2 target genes (FGF-4, Sox2, Oct-3/4, Nanog, Fbx15, and UTF1). The triangle represents possible inserts of up to 3 base pairs between the HMG and POU motifs. For example, the FGF-4 gene contains a 3 base pair insert between its HMG and POU motifs. For the remaining 5 genes, their HMG and POU motifs are directly adjacent to one another.

Figure 3

An expanded model for the regulation of Oct-3/4:Sox2 target genes. Sox2 and Oct-3/4 work together cooperatively to regulate their own transcription and the transcription of a large set of downstream target genes. This includes genes expressed in ES cells and those not expressed in ES cells.

Figure 4

Sox protein redundancy and the regulation of Oct-3/4:Sox target genes. Oct-3/4 is proposed to work in conjunction with Sox2, as well as Sox4, Sox11 and Sox15, in ES cells to regulate the transcription of the Oct-3/4 and Sox2 genes as well as the transcription of a large set of downstream target genes. Sox2 is also proposed to indirectly regulate the transcription of the Oct-3/4 gene by upregulating Nr5a2 and downregulating Nr2f2, which are positive and negative regulators of the Oct-3/4 gene, respectively. As indicated by the dotted lines, it remains to be determined whether Sox4, Sox11 or Sox15 influence the expression of the Oct-3/4 and Sox2 genes.

Figure 5

Elevating the expression of Sox2 reduces the expression of genes required for the self-renewal of ES cells. Elevating the levels of Sox2 in EC and ES cells reduces the expression of the Oct-3/4 gene and the expression of downstream Sox:Oct target genes, such as FGF-4, Nanog and UTF1. As indicated by the dotted lines, it is unclear whether Oct-3/4 continues to positively influence the expression of Oct-3/4:Sox2 target genes when Sox2 is overexpressed.

Figure 6

Oct-3/4 and Sox2 function as molecular rheostats. Increasing or decreasing the levels of either Sox2 or Oct-3/4 in ES cells promotes their differentiation. However, the spectra of cell types that form vary. The cell types formed were determined by markers expressed in the differentiated cell populations. TE: trophectoderm, Endo: Endoderm, Meso: Mesoderm, Ecto: Ectoderm.