Distinct proliferative and neuronal programmes of chromatin binding and gene activation by ASCL1 are cell cycle stage-specific

ASCL1 is a potent proneural factor with paradoxical functions during development, promoting both progenitor pool expansion and neuronal differentiation. How a single factor executes and switches between these potentially opposing functions remains to be understood. Using human neuroblastoma cells as a model system, we show that ASCL1 exhibits cell cycle phase-dependent chromatin binding patterns. In cycling cells, S/G2/M phase-enriched binding occurs at promoters of transcribed pro-mitotic genes, while G1 phase-enriched binding of ASCL1 is associated with the priming of pro-neuronal enhancer loci. Prolonged G1 arrest is further required to activate these ASCL1-bound and primed neuronal enhancers to drive neuronal differentiation. Thus, we reveal that the same transcription factor can control distinct transcriptional programmes at different cell cycle stages, and demonstrate how lengthening of G1 allows engagement of a differentiation programme by turning unproductive factor binding into productive interactions.