WDR5 serves in co-activation and influences genome targeting of KLF3

Krüppel-like Factor 3 (KLF3) is a member of the archetypal SP/KLF family of transcription factors that bind GC-rich elements and CACCC boxes in promoters and enhancers via three classical Zinc Fingers (ZFs) at or near their C-termini. KLF3 can both repress and activate transcription. It represses by recruiting CtBP co-repressors via its N-terminal domain but the mechanism by which it activates was unknown. Here we show KLF3 associates with WDR5 and this interaction is associated with gene activation. We also demonstrate that this interaction is required for proper genomic targeting of KLF3. This helps explain previous results indicating that both the C-terminal ZF DNA-binding domain and N-terminal functional domain are required for KLF3 to identify its target genes. This result adds to only a handful of examples that transcriptional co-regulators, in addition to facilitating activation and repression, can also influence target gene selection. RNA-seq, KLF3-V5, and WDR5 ChIP-seq in KLF3-null MEF cells rescued by overexpressing WT KLF3-V5 or R254A KLF3-V5