The sox family of transcription factors: versatile regulators of stem and progenitor cell fate

Abstract

Sox family transcription factors are well-established regulators of cell fate decisions during development. Accumulating evidence documents that they play additional roles in adult tissue homeostasis and regeneration. Remarkably, forced expression of Sox factors, in combination with other synergistic factors, reprograms differentiated cells into somatic or pluripotent stem cells. Dysregulation of Sox factors has been further implicated in diseases including cancer. Here, we review molecular and functional evidence linking Sox proteins with stem cell biology, cellular reprogramming, and disease with an emphasis on Sox2.

Figure 1. Sox2 expression in pluripotent, fetal and adult progenitor and stem cells

Sox2 is expressed throughout development, initially in pluripotent founder cells of the blastocyst and subsequently in ectodermal, endodermal and mesodermal progenitors as well as in primordial germ cells. Sox2 expression is maintained in fetal and adult tissues derived from Sox2+ fetal progenitor cells and marks stem/progenitor cells and in some cases also differentiated cells.

Figure 2. Antagonisms between Sox2 and other lineage transcription factors determines cell fate

During organogenesis, Sox2 influences cell fate by inhibiting transcription factors that specify alternative cell lineages. Sox2 is expressed in an inverse gradient with the respective other transcription factor, and thus acts in a dosage-dependent manner to establish cellular identities within and boundaries between future tissues.

Figure 3. Sox factors as inducers of cellular reprogramming

Examples of Sox factors whose enforced expression in other cell types induces dedifferentiation. (A) Ectopic expression of Sox2 in combination with Klf4, Oct4 and c-Myc endows somatic cells with pluripotency, giving rise to induced pluripotent stem cells (iPSCs). (B) Sox2 expression alone, or together with other factors reprograms fibroblasts into induced neural stem cells (iNSCs). (C) Sox9 expression in differentiated luminal cells generates luminal progenitors, and in combination with Slug expression, converts them into mammary stem cells capable of generating an entire mammary ductal tree when transplanted into a mammary fat pad. (D) Sox17 expression in adult hematopoietic stem and progenitor cells induces a fetal-like hematopoietic stem cell state. These cells have increased self-renewal potential and express HSC markers. However, long term Sox17 expression in the adult leads to leukemogenesis.

4. Mechanisms by which Sox2 controls self-renewal and differentiation in pluripotent and multipotent stem cells

(A) Sox2 activates self-renewal genes and represses differentiation genes in a cell type-specific manner by (i) interpreting tissue-specific signals and (ii) interacting with other cell type-specific cofactors. For example, in ESCs Sox2 occupies many targets containing Oct4-Sox2 consensus sequences and partners with downstream effectors of ESC-specific signaling pathways including Stat3 (LIF pathway). In NPCs, Sox2 occupies target genes that also contain binding sites for the brain-specific factors Brn2 and Chd7, thus activating different sets of genes. In addition, Sox2 activates its own transcription and regulates components of the signaling pathways that control self-renewal, thereby promoting maintenance of the undifferentiated state. (B) In addition to activating self-renewal genes and suppressing lineage-specific genes, Sox2 acts as a pioneer factor to prime stem cells for subsequent gene activation. Sox2 occupies silent NPC genes in ESCs, which carry bivalent domains poised for gene activation. Upon differentiation into NPCs, Sox2 and Sox3 cooperate to activate self-renewal genes while keeping neuronal differentiation genes in a silent but bivalent state. When NPCs undergo terminal differentiation, Sox2 and Sox3 disengage from neuronal-specific enhancers and are replaced by Sox11.