Cell fate acquisition and reprogramming by the proneural transcription factor ASCL1.

ASCL1 is a key member of the proneural basic helix-loop-helix (bHLH) transcription factor (TF) family and it plays diverse roles in nervous system development and maintenance. ASCL1 is also one of the most studied bHLH TFs in the field of somatic cell reprogramming, as it can reconfigure the chromatin of the cell of origin to impose a neuronal identity. However, the ability of ASCL1 to drive neuronal fate does not come without exceptions, as there are cell types that are refractory to ASCL1-mediated reprogramming, and there are developmental contexts where ASCL1 does not drive neurogenesis but supports the generation of other lineages. ASCL1 has also emerged as an important player in cancers like neuroblastoma and glioblastoma, underscoring the clinical need for a robust understanding of how ASCL1 controls cell identity. In this review, we revisit the foundational studies that established ASCL1 as a critical regulator of neuronal differentiation and incorporate recent advances in our understanding of ASCL1 post-translational regulation and transcriptional control. By integrating these perspectives, this review provides a comprehensive overview of the diverse roles of ASCL1 in development, reprogramming and cancer, offering insights into its molecular functions and therapeutic potential.