The transcriptional consequences of inhibiting CDK8 in the context of innate immune activation

TF-seq analysis conducted on the same set of lysates identified 3 primary pathways modulated by CDK8 inhibition: suppression of NF-kB and STAT1 and de-repression of AP-1. The results with STAT1 are consistent with literature identifying a role for CDK8 in IFN-driven STAT1 transcriptional activation. In addition, there is patent literature indicating that CDK8 inhibition can suppress NF-kB activation. We expect to see changes in the global RNA-seq expression profiles consistent with the TF-seq data – namely, reduced expression of NF-kB and STAT1 target genes. Overall design: BMDMs were pre-treated with the CDK8 inhibitors dCA (100 nM), or BRD-6989 (1 uM) for 24 hours, then stimulated with a cohort of 11 different TLR ligands for 8 time points from 0-4 hours.