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Mediator, a large complex highly conserved throughout eukaryotes, is preeminently responsible for transcription pre-initiation complex assembly and for conveying regulatory signals.Mediator subunits have been suggested to be organized into three functional modules, Head, Middle and Tail, and the modular architecture and subunit composition are conserved from yeast to human.Due to the complexity, flexibility and modularity of the core Mediator, many basic questions, such as the boundaries of the three modules, and how they interact with each other to enable regulation of transcription, remain unresolved.To illuminate the modular architecture, we divided Mediator into modules or module assemblage and characterize the structures and functions individually.We compared the EM structures of the core Mediator and its subcomplex, especially the first 3D structure of the Head +Middle modules, performed nanogold labeling of multiple subunits from different modules, and proposed a new modular organization of Mediator, which resolves many inconsistencies of the previous model with the biochemical and functional studies.The redefined model allowed us to integrate the structural and functional information into a coherent mechanism for Mediator modularity and regulation in transcription initiation.Moreover, we studied in details the substantially conformational and compositional heterogeneity of the Head +Middle modules, and illuminate the interaction surface between Head and Middle modules.