Unexplored roles of corepressors in transcriptional regulation and in epigenetic disease mechanisms

The purpose of our research is to contribute to a deeper understanding of closely linked transcriptional and epigenetic mechanisms underlying health and disease.

We are particularly interested in the role of coregulators, which via controlling transcription factors and chromatin states are essential components of these mechanisms.With an emphasis on a fundamental corepressor complex implicated in metabolic and inflammatory disease pathways, we recently made the unexpected discovery that corepressors operate at both enhancers and silencers to trigger alternative macrophage gene expression programs.Here we propose research within three aims to address the following key hypotheses emerging from this discovery:Corepressors are essential components of topologically associating domains (TADs) to control chromatin dynamics and transcription, in cooperation with transcription factors and other coregulators.Corepressors mark TAD-intrinsic silencers in different signaling contexts and can be exploited for genome-wide silencer screenings.Corepressor alterations trigger epigenetic remodeling and memory mechanisms that causally link type 2 diabetes to cardiovascular diseases such as atherosclerosis.