Mediator condensates localize signaling factors to key cell identity genes. Zamudio et al. S1

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.

定义每个细胞身份的基因表达程序受主转录因子（TFs）的控制，这些主转录因子与细胞特异性增强子以及信号因子相结合，后者将这些细胞外刺激传递至这些增强子。近期研究揭示了主转录因子与Mediator辅助激活因子在超级增强子区域形成相分离的凝聚体。本研究提供了证据表明，WNT、TGF-β和JAK/STAT通路中的信号因子利用其内在无序区域（IDRs）进入并集中于超级增强子区域的Mediator凝聚体中。我们展示了WNT辅助激活因子β-连环蛋白与凝聚体成分以及DNA结合因子相互作用，以选择性占据与超级增强子相关的基因。我们提出，细胞对信号的反应特异性部分由信号因子的IDRs介导，这些IDRs导致这些因子在主转录因子和Mediator在具有显著细胞身份角色基因上建立的凝聚体中分离。