Set1 promotes Notch-induced transcriptional activation.

UNLABELLED: Notch is a highly conserved transmembrane receptor essential for organ development and homeostasis. Dysregulation of Notch signaling has been implicated in numerous human diseases. Upon ligand binding, the intracellular domain of Notch (NICD) is released from cell membrane and enters the nucleus, where it binds to CSL transcription factors to activate transcription of target genes. Drosophila wing is a commonly-used model system to investigate Notch signaling regulation. In this study, we demonstrate that reduced expression of Set1, which catalyzes H3K4 trimethylation, results in adult wings with reduced size and thickened veins. Mechanistic study using both Drosophila and human cells reveals that Set1 promotes Notch signaling by enhancing association of NICD and its cofactors to the target genes. Furthermore, knocking down Set1 suppresses NICD-induced overgrowth in Drosophila wing discs and eyes and inhibits proliferation and survival of human T-cell acute lymphoblastic leukemia cells that exhibit Notch hyperactivation. In summary, our work identifies Set1 as a positive regulator of Notch signaling and a potential therapeutic target for Notch-driven malignancies.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-026-06123-2.