Mediator condensates localize signaling factors to key cell identity genes. Zamudio et al.
The gene expression programs that define each cell’s identity are controlled by master transcription factors (TFs) that bind cell-type specific enhancers, as well as signaling factors, which bring extracellular stimuli to these enhancers. Recent studies have revealed that master TFs form phase-separated condensates with the Mediator coactivator at super-enhancers. Here we present evidence that signaling factors for the WNT, TGF-β and JAK/STAT pathways employ their intrinsically disordered regions (IDRs) to enter and concentrate in Mediator condensates at super-enhancers. We show that the WNT coactivator β-catenin interacts both with components of condensates and DNA binding factors to selectively occupy super-enhancer associated genes. We propose that the cell-type specificity of the response to signaling is mediated, in part, by the IDRs of the signaling factors, which cause these factors to partition into condensates established by the master TFs and Mediator at genes with prominent roles in cell identity.