| dc.description.abstract | WDR5 is a highly-conserved nuclear protein which facilitates the assembly of histone-modifying complexes involved in a variety of chromatin-based, gene regulatory processes. WDR5 is best known for its role in scaffolding the assembly of MLL/SET histone methyltransferase complexes that catalyze histone H3 lysine 4 (H3K4) di– and tri-methylation (Me2/Me3), but WDR5 acts outside this setting to promote ribosomal protein gene transcription and recruit the oncogenic transcription factor MYC to chromatin. WDR5 is also a target for pharmacological inhibition in cancer, and most drug discovery efforts aim to block the WIN site of WDR5, an arginine binding cavity that engages MLL/SET enzymes. Therapeutic application of WIN site inhibitors is complicated by the disparate functions of WDR5, but is generally guided by two assumptions—that WIN site inhibitors disable all functions of WDR5, and that changes in H3K4me drive the transcriptional response of cancer cells to WIN site blockade. Here, we test these assumptions by comparing the impact of WIN site inhibition versus WDR5 degradation on H3K4me and transcriptional processes in Burkitt lymphoma and neuroblastoma cell lines. We show that WDR5 regulates transcription widely, yet WIN site inhibition disables only a specific subset of WDR5 activity, and that H3K4me changes induced by WDR5 depletion do not explain accompanying transcriptional responses. Additionally, WDR5 degradation results in the collateral loss of SET1/MLL proteins. These data recast WIN site inhibitors as selective loss-of-function agents, contradict H3K4me as a relevant mechanism of action for WDR5 inhibitors, and point to distinct clinical applications of WIN site inhibitors and WDR5 degraders. | |
