Novel functions of Mediator kinases in immune cells to prevent auto-immune disease

The Mediator complex with its catalytic subunit the Mediator kinase module, composed of CDK8/19 and other members, is multimeric complex regulating the transcription machinery, transcription factor activity at promoter and enhancer regions and the chromatin landscape, thus controlling gene expression and cell lineage differentiation. While CDK8 and CDK19 are commonly dysregulated in cancers, we recently discovered that they are essential to maintain lung function. Mice with deletion full-body deletion of CDK8 and CDK19 display inflammation in the liver and lung, characterised by pronounced lymphocyte infiltrations. This project aims to investigate how and in which cell type Mediator kinase are required to prevent auto-immune driven inflammation. To this extent, we will utilise our exiting scRNA-seq data from the lung, spleen and lymph nodes of DKO to first, characterise changes in inflammatory signalling across immune cell types and second, infer gene regulatory networks to identify CDK8/19-regulated transcription factors and regulatory gene networks. Potential targets will then be investigated with targeted epigenetic and transcriptomic approaches such as ATAC-seq, RNA-seq and Cut&Run on isolated immune cell populations.