POU4F3 pioneer activity enables ATOH1 to drive diverse mechanoreceptor differentiation through a feed-forward epigenetic mechanism

Significance Embryonic development relies on a hierarchy of transcription factor expression and chromatin structure changes to establish unique patterns of gene expression in different cell types. The mechanisms regulating these changes are poorly understood. We compared two mechanosensory cell types, inner ear hair cells and epidermal Merkel cells, to demonstrate a feed-forward mechanism involving the transcription factors ATOH1, a “master regulator” of differentiation, and POU4F3 during mechanosensory differentiation. We show that downstream POU4F3 pioneer factor activity allows ATOH1 to access much of its enhancer network in developmentally closed chromatin. Our data suggest this shared feed-forward mechanism preceded the evolutionary divergence of hair cells and Merkel cells from an ancient mechanosensory receptor type and thus may have enabled their divergence.