Context-Dependent Wiring of Sox2 Regulatory Networks for Self-Renewal of Embryonic and Trophoblast Stem Cells

Abstract

Sox2 is a transcription factor required for the maintenance of pluripotency. It also plays an essential role in different types of multipotent stem cells, raising the possibility that Sox2 governs the common stemness phenotype. Here we show that Sox2 is a critical downstream target of fibroblast growth factor (FGF) signaling, which mediates self-renewal of trophoblast stem cells (TSCs). Sustained expression of Sox2 together with Esrrb or Tfap2c can replace FGF dependency. By comparing genome-wide binding sites of Sox2 in embryonic stem cells (ESCs) and TSCs combined with inducible knockout systems, we found that, despite the common role in safeguarding the stem cell state, Sox2 regulates distinct sets of genes with unique functions in these two different yet developmentally related types of stem cells. Our findings provide insights into the functional versatility of transcription factors during embryogenesis, during which they can be recursively utilized in a variable manner within discrete network structures.

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

“…The period of loss of NANOG expression occurring at peri‐implantation (Chambers et al , 2003; Acampora et al , 2013) may enable cells of the epiblast to downregulate a number of pivotal naïve pluripotency determinants, including ESRRB (Adachi et al , 2013). In the post‐implantation epiblast, NANOG is re‐expressed (Hart et al , 2004; Osorno et al , 2012; Hoffman et al , 2013) but ESRRB is not (Adachi et al , 2013), likely due to differences in signaling environments between pre‐ and post‐implantation epiblasts. It is noteworthy that subpopulations of ESC cultures have been proposed to bear a similar character to primed pluripotent cells and vice versa (Hayashi et al , 2008; Han et al , 2010).…”

Ube2s regulates Sox2 stability and mouse ES cell maintenance

“…43 In trophoblast stem cells, Sox2 cooperates with Tfap2c to orchestrate the unique transcription profiles underpinning the corresponding functional properties of these cells. 47 Of note, the role of Sox2 is highly dosagedependent. 4,44 In ES cells, both elevation and depletion of Sox2 results in cell differentiation.…”

Elf5-centered transcription factor hub controls trophoblast stem cell self-renewal and differentiation through stoichiometry-sensitive shifts in target gene networks

“…Trophoblast stem cells (TSCs) are a stem cell type representative of the extraembryonic placental lineage most akin to cells in the extraembryonic ectoderm (ExE), a structure that eventually gives rise to specialized placental cell types (Tanaka et al 1998;Adachi et al 2013). TSCs can self-renew and remain multipotent in the presence of fibroblast growth factor (Fgf) and embryonic fibroblast-conditioned medium (CM).…”

“…A number of TFs are known to be involved in either the determination of trophoblast cell fate and/or the ability to derive or maintain TSCs. Among these are the TEA domain family member Tead4 (Yagi et al 2007;Nishioka et al 2008), the caudal-type homeobox factor Cdx2, the Tbox gene Eomes, the SRY-box gene Sox2, and the estrogen-related receptor Esrrb (Russ et al 2000;Tremblay et al 2001;Avilion et al 2003;Strumpf et al 2005;Ralston and Rossant 2008;Adachi et al 2013;Latos et al 2015). Other TFs important for the establishment of a self-renewing TSC population include the AP-2 family member Tfap2c (Auman et al 2002;Werling and Schorle 2002), the Ets family members Ets2 and Elf5 (Yamamoto et al 1998;Donnison et al 2005), and the Gata motif-containing factor Gata3 (Home et al 2009;Ralston et al 2010).…”

“…Genome-wide occupancy analyses of Cdx2, Elf5, Eomes, Ets2, Tfap2c, Gata3, Sox2, and Esrrb in TSCs revealed that they cobind a significant number of target loci, including themselves, to establish a self-reinforcing TSC-specific transcriptional network (Kidder and Palmer 2010;Adachi et al 2013;Chuong et al 2013;Latos et al 2015). However, despite coexpression in the TSC compartment in vivo and in vitro, the precise temporal and spatial expression domains of these various TFs are not fully overlapping.…”