Distinct proliferative and neuronal programmes of ASCL1 chromatin binding and gene activation are cell cycle stage dependent [RNA]

ASCL1 is a potent proneural factor with opposing functions during development, promoting both neuronal progenitor pool expansion and terminal differentiation. How one factor can execute, and switch between, such contradictory functions remain to be elucidated. Using neuroblastoma cells as a model system, we show that ASCL1 exhibits cell cycle phase dependent binding patterns, where G1 phase enriched binding is associated with the priming of pro-neuronal enhancer loci, while SG2M phase enriched binding occurs at promoters of transcribed pro-mitotic genes. Prolonged G1 arrest activates ASCL1-bound and primed neuronal enhancers to drive terminal cell differentiation of these neuroblastic progenitor cells. These findings further our understanding of a key developmental factor, with implications for reprogramming and pathologies such as neuroblastoma.