Dissecting OCT4 defines the role of nucleosome binding in pluripotency maintenance

The aim of this study is to dissect the transcription factor OCT4 and reveal which parts of the protein are essential for interaction with nucleosomes and access to closed chromatin. We revealed that the DNA-binding domain mediates the interaction of OCT4 with nucleosomes. Remarkably, nucleosome-binding can be uncoupled from DNA-binding, diminishing the ability of OCT4 to access to closed chromatin, thus losing the pioneer function. We show that the pioneer function of OCT4 is not only essential during reprogramming differentiated cells to pluripotency but also during pluripotency maintenance of embryonic stem cells. Overall, this study shows how pioneer transcription factors interact with nucleosomes to engage the genome and control cellular identity, highlighting that nucleosomes are not always barriers to genome accessibility.