OCT4-SOX2 dimers reshape the epigenome to promote neural crest multipotency [CUT&RUN]. OCT4-SOX2 dimers reshape the epigenome to promote neural crest multipotency [CUT&RUN]

The transcription factors OCT4 and SOX2 play an essential role in the establishment and maintenance of pluripotent embryonic stem cells (ESCs). Yet, their function in specialized stem cell populations is still poorly understood. Here, we show that the OCT4 and SOX2 work as dimers to regulate the epigenomic landscape of neural crest cells. By isolating primary neural crest cells at a range of developmental stages, we characterized the transcriptomic and epigenomic changes that take place during specification, migration, and early differentiation. Analysis of these datasets revealed that the OCT4/SOX2 dimer promotes an epigenomic signature inherent to the multipotent neural crest. We found that the emergence of this epigenomic state requires the translocation of OCT4/SOX2 to tissue-specific cis-regulatory regions. By examining genome organization during the induction of hESCs into neural crest cells, we observed that the patterns of genomic occupancy of the dimer are modified during cell fate commitment. Dimer translocation is guided by neural crest-specific pioneer transcription factors, which physically interact with the OCT4/SOX to modify their genomic targets. Our results demonstrate how the ESC pluripotency program is repurposed in specialized stem cells to control chromatin organization and define the developmental potential of embryonic progenitors. Overall design: CUT&RUN