TFAP2C regulates transcription in human naive pluripotency by opening enhancers

Naïve and primed pluripotent hESCs bear transcriptional similarity to pre- and post-implantation epiblast and thus constitute a developmental model for understanding the earliest pluripotent stages in human embryo development. To identify new transcription factors that differentially regulate the unique pluripotent stages, we mapped open chromatin using ATAC-Seq and found enrichment of the AP2 transcription factor binding motif at naïve-specific open chromatin. We determined that the AP2 family member TFAP2C is upregulated during primed to naïve reversion and becomes widespread at naïve-specific enhancers. TFAP2C functions to maintain pluripotency and repress neuroectodermal differentiation during the transition from primed to naïve by facilitating the opening of enhancers proximal to pluripotency factors. Additionally, we identify a previously undiscovered naïve-specific POU5F1 (OCT4) enhancer enriched for TFAP2C binding. Taken together, TFAP2C establishes and maintains naïve human pluripotency and regulates OCT4 expression by mechanisms that are distinct from mouse.