To proliferate or to differentiate: a cell cycle decision Free

Achaete-Scute homolog 1 (ASCL1) is a proneural transcriptional regulator that modulates both proliferation and differentiation programmes of immature nerve cells, called neuroblasts, during development. Although previous studies have suggested that ASCL1 function may be differentially controlled during different stages of the cell cycle in neuroblastoma (a type of cancer that starts in neuroblasts), the mechanisms underlying the paradoxical functions of ASCL1 in proliferation and differentiation remain unclear. Here, Beckman and colleagues find that ASCL1 binds to loci associated with both neuronal and proliferative genes in neuroblastoma cells. Further, live imaging, chromatin immunoprecipitation and RNA-sequencing analyses reveal that ASCL1 binds to pro-neurogenic enhancers during the G1 phase of the cell cycle, but it can't drive neuronal gene expression in cycling neuroblasts. As cells progress through the DNA synthesis, G2 and mitotic (S/G2/M) phases, ASCL1 preferentially associates with pro-proliferative genes and upregulates their expression levels. However, prolonged arrest of neuroblastoma cells at G1 phase - the hallmark of a pro-differentiation state - facilitates accumulation of the epigenetic marker H3K27ac at ASCL1-bound G1-enriched sites and allows pro-neuronal gene expression. Overall, this work reveals that ASCL1 controls both cell proliferation and differentiation in a cell cycle-stage-dependent manner.