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].