NOTCH1–RBPJ complexes drive target gene expression through dynamic interactions with superenhancers

Studies focused on understanding how transcription factors control gene expression have shown that transcription-factor binding sites generally greatly exceed the number of regulated genes, making it challenging to identify functional binding sites. Using Notch pathway inhibitors, we identified a subset of Notch-binding sites in leukemia cell genomes that are dynamic, changing in occupancy relatively rapidly when Notch signaling is perturbed. Dynamic Notch sites are highly associated with genes that are directly regulated by Notch and mainly lie in large regulatory switches termed superenhancers, which control genes with key roles in development and cancer. This work links Notch signaling to superenhancers and suggests that assessment of transcription factor–genome dynamics can help to identify functionally important regulatory sites.