Set1 promotes Notch-induced transcriptional activation

Notch is a highly conserved transmembrane receptor essential for organ development and homeostasis. Dysregulation of Notch has been implicated in various types of human cancers. Upon ligand binding, the intracellular domain of Notch (NICD) is released and translocated into the nucleus and activates transcription of the target genes by interacting with CSL transcription factors. Drosophila wing is a commonly used model system to investigate Notch signaling activity as this pathway is required for proper wing growth and patterning. In this study, we demonstrate that reduced expression of Set1, which catalyzes methylation of lysine 4 on histone H3, results in adult wings with decreased size and thickened veins. Genetic interaction between Notch and Set1 in wing development, coupled with the observed downregulation of Notch target genes in Set1 mutant wing discs suggest that Set1 functions as a positive regulator of Notch signaling. Mechanistic study using both Drosophila wing disc and mammalian cells reveals a conserved role of Set1 in enhancing association of NICD and its cofactors to the target genes to strengthen transcription. Furthermore, knocking down Set1 suppresses NICD-induced overgrowth in Drosophila wing discs and eyes as well as proliferation and survival of human T-cell acute lymphoblastic leukemia cells with Notch hyperactivation. In summary, our work identifies Set1 as a positive regulator of Notch signaling and a potential therapeutic target for Notch-driven malignancies.