GSE173207
Action of WDR5 and HDM2 inhibitors in SMARCB1-deficient cancer cells
Rhabdoid tumors (RT) are rare and aggressive pediatric tumors that are driven by the loss the tumor suppressor SNF5 (SMARCB1). Here we examine how RT cells respond to small molecule-mediated inhibitors of the “WIN” site of WDR5, a chromatin-associated protein that regulates a specific set of genes linked to protein synthesis. We characterize WDR5 binding in RT cell lines via ChIP-Seq and show that WIN site inhibitor rapidly and comprehensively displaces WDR5 from chromatin in these cells. Using Precision Run On-sequencing (PRO-Seq) we show that WDR5-bound protein synthesis genes are early and direct transcriptional targets of WIN site inhibitor. We also use RNA-Seq to characterize the persistent transcriptional changes in RT lines treated with WIN site inhibitor, and compare these transcriptional effects with those of the HDM2 inhibitor nutlin-3a. Overall design: G401, TTC642, KYM-1, TTC549, or TM87-16 cells were treated with DMSO or WIN site inhibitor C16. ChIP-Seq was used to track interaction of WDR5 with chromatin; PRO-Seq was used to track early changes in the distribution of active RNA polymerases, and RNA-Seq was used to monitor long-term transcriptional changes. RNA-Seq was also performed on G401, TTC642, and KYM-1 cells treated with the HDM2 inhibitor nutlin-3a