What makes a pluripotency reprogramming factor?

Resetting differentiated cells to a pluripotent state is now a widely applied technology and a key step towards personalized cell replacement therapies. Conventionally, combinations of transcription factor proteins are introduced into a differentiated cell to convert gene expression programs and to change cell fates. Yet, the molecular mechanism of nuclear reprogramming is only superficially understood. Specifically, it is unclear what sets pluripotency reprogramming factors (PRFs) molecularly apart from other transcription factor molecules that induce, for example, lineage commitment in embryonic development. Ultimately, PRFs must scan the genome of a differentiated cell, target enhancers of pluripotency factors and initiate gene expression. This requires biochemical properties to selectively recognize DNA sequences, either alone or by cooperating with other PRFs. In this review, we will discuss the molecular make-up of the prominent PRFs Sox2, Oct4, Klf4, Esrrb, Nr5a2 and Nanog and attempt to identify unique features distinguishing them from highly homologous yet functionally contrasting family members. Except for Klf4, the consensus DNA binding motifs are highly conserved for PRFs when compared to non-pluripotency inducing family members, suggesting that the individual DNA sequence preference may not be the distinguishing factor. By contrast, variant composite DNA motifs were found in pluripotency enhancers that lead to a differential assembly of various Sox and Oct family members due selective protein-protein interaction platform. As a consequence, the cooperation of PRFs on distinctly configured DNA motifs may underlie the reprogramming process. Indeed, it has been demonstrated that Sox17 can be rationally engineered into a PRF by modulating its cooperation with Oct4. An in deep understanding of this phenomenon would allow rational engineering and optimization of PRFs. This way, the reprogramming efficiency can be enhanced and fine-tuned to generate optimal synthetic reagents for regenerative medicine.