Evolutionary origin of vertebrate OCT4/POU5 functions in supporting pluripotency

The support of pluripotent cells over time is an essential feature of development. In eutherian embryos, pluripotency is maintained from naive states in peri-implantation to primed pluripotency at gastrulation. To understand how these states emerged, we reconstruct the evolutionary trajectory of the Pou5 gene family, which contains the central pluripotency factor OCT4. By coupling evolutionary sequence analysis with functional studies in mouse embryonic stem cells, we find that the ability of POU5 proteins to support pluripotency originated in the gnathostome lineage, prior to the generation of two paralogues, Pou5f1 and Pou5f3 via gene duplication. In osteichthyans, retaining both genes, the paralogues differ in their support of naive and primed pluripotency. The specialization of these duplicates enables the diversification of function in self-renewal and differentiation. By integrating sequence evolution, cell phenotypes, developmental contexts and structural modelling, we pinpoint OCT4 regions sufficient for naive pluripotency and describe their adaptation over evolutionary time. By constructing an evolutionary trajectory of the cyclostome-gnathostome Pou5 gene family and comparing the structural and phenotypic protein variations, the authors uncover the origin of functional characteristics for the pluripotency factor Oct4.

Automated summary

This study reconstructs the evolutionary trajectory of the Pou5 gene family and finds that the ability of POU5 proteins to support pluripotency originated in the gnathostome lineage. The specialization of the paralogues Pou5f1 and Pou5f3 in osteichthyans enables the diversification of function in self-renewal and differentiation. The study also identifies the OCT4 regions sufficient for naive pluripotency and describes their adaptation over evolutionary time.