Key features of the POU transcription factor Oct4 from an evolutionary perspective

Abstract

Oct4, a class V POU-domain protein that is encoded by the Pou5f1 gene, is thought to be a key transcription factor in the early development of mammals. This transcription factor plays indispensable roles in pluripotent stem cells as well as in the acquisition of pluripotency during somatic cell reprogramming. Oct4 has also been shown to play a role as a pioneer transcription factor during zygotic genome activation (ZGA) from zebrafish to human. However, during the past decade, several studies have brought these conclusions into question. It was clearly shown that the first steps in mouse development are not affected by the loss of Oct4. Subsequently, the role of Oct4 as a genome activator was brought into doubt. It was also found that the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) could proceed without Oct4. In this review, we summarize recent findings, reassess the role of Oct4 in reprogramming and ZGA, and point to structural features that may underlie this role. We speculate that pluripotent stem cells resemble neural stem cells more closely than previously thought. Oct4 orthologs within the POUV class hold key roles in genome activation during early development of species with late ZGA. However, in Placentalia, eutherian-specific proteins such as Dux overtake Oct4 in ZGA and endow them with the formation of an evolutionary new tissue-the placenta.

Keywords: ESCs; NSCs; Oct4; Pluripotency; Reprogramming; Zygotic genome activation; iPSCs.

Fig. 1

POU-domain binding to DNA and dimerization. “S” stands for the POUs subdomain and “H” for the POUh subdomain. Pins and pyramids with corresponding recesses represent special contacts responsible for PORE and MORE binding, respectively. a Monomer POU DNA binding with opposite localization of subdomains, b POU homodimerization on the PORE, mediated by I21 of POUs; subdomains bind opposite sides of the  DNA as in monomer binding, c POU heterodimerization on the MORE, mediated by S151; subdomains bind perpendicular faces of the DNA instead of opposite sides, d POU heterodimerization with the HMG domain on the Sox-Oct element, partially mediated by I21 from the POUs subdomain

Fig. 2

a Conservation of functional amino acids in POUV proteins across vertebrates; three main subgroups of POU domain–containing proteins are represented (Pou5f1 orthologs and Pou5f3 orthologs from different species, and several examples of POUV paralogs); other classes of POU domain–containing proteins from mouse, b potential Sox-Oct element near chicken Sox3 gene (mSox: mouse Sox gene, cSox: chicken Sox gene); Fgf4 and Utf1 regulatory regions were taken as examples; green-colored letters mean permissive nucleotides for SoxB or POUV binding, red-colored letters mean less suitable for HMG-POU binding

Fig. 3

POUV role in genome activation: a Initial local DNA opening by HMG-POU complex, along with Nanog, b recruitment of chromatin modifiers such as BRG and acetyltransferases to this locus, c expansion of DNA opening with the subsequent emergence of a poised state, which is characterized by an ability to respond to different external signals, d recruitment of transcriptional machinery and the onset of transcription

Fig. 4

Mammals are characterized by the presence of a new regulatory superstructure that provides earlier ZGA for novel tissue (trophectoderm) differentiation. Activators such as Nfya and Dux overtake Oct4-Sox2-Nanog in mammalian ZGA and hence allow for an early launch of the first differentiation event, in this case trophectoderm specification. At the blastocyst stage, the inner cell mass is reminiscent of a time point of zebrafish and xenopus ZGA