Mediator kinase inhibition suppresses hyperactive interferon signaling in Down syndrome I

Individuals with Down syndrome have a increased likelihood of suffering from inflammatory and autoimmune conditions, due to the presence of four interferon receptors on chromosome 21. Transcription of genes plays a key role in the interferon response, and the Mediator kinases, CDK8 and CDK19, are essential in potentiating this transcription. Given the role CDK8/19 play in the interferon response, and the fact that selective inhibitors of these kinases exist (such as Cortistatin A), it is possible that targetting Mediator kinase activity may alleviate symptoms of chronic inflammation in Down syndrome. Immortalized lymphoblastoid cells from a pair of brothers, one with Down syndrome and one without, were pre-treated for 30 minutes with either vehicle (10% DMSO) or 100 nM Cortistatin A. After pre-treatment, they were subsequently exposed to either vehicle (40 mM Tris pH 7.4) or 10 ng/mL IFNgamma. After 45 minutes of exposure to vehicle or IFN, nuclei were isolated from cells and nuclear run-on reactions containing biotinylated CTP were performed. Nascent RNA was captured using strepdavidin, and RNA from each condition was reverse-transcribed into cDNA and labeled with unique indices for sequencing.