Linking gene expression and genome organisation

Chromatin remodelling complexes are essential for life. They organise the chromatin landscape and set the foundation for vital cellular processes including cell lineage differentiation. Despite their importance, the mechanisms coordinating their activity present a large knowledge gap, limiting our understanding of fundamental biological processes. This project will investigate how a core member of the gene expression machinery, called the Mediator complex, regulates the activity of chromatin remodellers during cellular homeostasis and differentiation and therefore, will establish the gene expression machinery as a novel regulator of the chromatin landscape. The Mediator is a multimeric protein complex which fine-tunes transcription by integrating upstream signals from transcription factors to RNA polymerase II. The Mediator reversibly interacts with the so-called Mediator kinase module (MKM), which is a four-subunit complex that acts as the catalytic active part of the Mediator. We have recently showed that the MKM as part of the Mediator interacts and phosphorylates members of the chromatin remodelling SWI/SNF complex (ARID1A) and the NuRD complex (CHD4). Surprisingly, ARID1A chromatin binding was drastically reduced in CDK8/19-deficient IECs, suggesting that the Mediator controls SWI/SNF chromatin occupancy. Here, we will characterise the functional relevance of this interaction and its contribution to 3D genome organisation in the context of cell lineage differentiation systematically using genetic mouse model, organoid cultures in combination with functional genomic approaches.