Effect of ASCL1 phosphorylation status on chromatin binding and target regulation in neuroblastoma

ABSTRACT: ASCL1, a basic helix-loop-helix family transcription factor, is a master regulator of developmental neurogenesis and a crucial component of transcription factor cocktails that can convert heterologous cell types such as fibroblasts into neurons. The ability of ASCL1 to drive neuronal differentiation is controlled by multi-site phosphorylation but how this modification controls the genome-wide transcriptional activity of ASCL1 is unknown. Using human neuroblastoma cells that maintain a rapidly dividing neuroblastic phenotype yet retain the ability to undergo differentiation as a model system, we find that phosphorylation of ASCL1 has limited effect on target gene promoter association, but predominantly regulates its binding to a subset of distal enhancer regions, resulting in extensive differences in target control by activation, as well as direct and indirect gene repression. These genome-wide analyses reveal how post-translational modification of ASCL1 can change its structure and function, driving it to differential regulatory elements to change cell fate, and controlling ASCL1’s activity as a master transcription regulator of neurogenesis. Using functional mutational and pharmacological approaches, we find that preventing CDK-dependent phosphorylation of ASCL1 in neuroblastoma cells results in co-ordinated suppression of the MYC-driven core circuit supporting neuroblast identity and proliferation, while simultaneously activating a gene programme driving neuronal differentiation. Thus, we show targeting the post-translational modification of a key developmental regulator can re-engage a latent genome-wide programme forcing mitotic exit and differentiation in cancer cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE153823 | GEO | 2021/03/15

REPOSITORIES: GEO