GSE136451
WDR5 is a conserved regulator of protein synthesis gene expression
WDR5 is a highly-conserved nuclear protein that performs multiple scaffolding functions in the context of chromatin. WDR5 is also a promising target for pharmacological inhibition in cancer, with small molecule inhibitors of an arginine-binding pocket of WDR5 (the "WIN" site) showing efficacy against a range of cancer cell lines in vitro. Efforts to understand WDR5, or establish the mechanism of action of WIN site inhibitors, however, are stymied by its many functions in the nucleus, and a lack of knowledge of the conserved gene networks—if any—that are under its control. Here, we have performed comparative genomic analyses to identify the conserved sites of WDR5 binding to chromatin, and the conserved genes regulated by WDR5, across a diverse panel of cancer cell lines. We show that a specific cohort of protein synthesis genes (PSGs) are invariantly bound by WDR5, demonstrate that the WIN site anchors WDR5 to chromatin at these sites, and establish that PSGs are both acute and persistent targets of WIN site blockade. Together, these data reveal that WDR5 plays a predominant transcriptional role in biomass accumulation and reinforce the notion that WIN site inhibitors kill sensitive cancer cells by disrupting protein synthesis homeostasis. Overall design: ChIP-Seq was used to track the interaction of WDR5 with chromatin in LoVo, Be2C, MC38, and 3T3 cells. ChIP-seq in LoVo cells includes 2 IgG (control) biological replicates, and 2 WDR5 biological replicates. ChIP-seq in Be2C, MC38, and 3T3 cells includes 3 IgG (control) biological replicates and 3 WDR5 biological replicates. For RNA studies, either LoVo or CHP134 cells were treated with the WIN site inhibitor C6, or DMSO (control). SLAM-Seq was used to monitor early transcriptional changes in LoVo cells after 4 hours of treatment with DMSO or 25 uM C6 - 3 DMSO-treated biological replicates and 3 C6-treated biological replicates are included. RNA-Seq was used to monitor transcriptional changes in CHP134 cells after 24 hours of treatment with DMSO or 5 uM C6 - 3 DMSO-treated biological replicates and 3 C6-treated biological replicates are included.