Coactivator condensation at super-enhancers links phase separation and gene control

• DOI: 10.1126/science.aar3958
• Publication Date: 2018-06-21T18:06:25Z
• Authors: Benjamin R. Sabari; Alessandra Dall’A...; Ann Boija; Isaac A. Klein; Eliot L. Coffey; Krishna Shrinivas; Brian J. Abraham; Nancy M. Hannett; Alicia V. Zamudio; John C. Manteiga; Charles H. Li; Yang E. Guo; Daniel S. Day; Jurian Schuijers; Eliza Vasile; Sohail Malik; Denes Hnisz; Tong Ihn Lee; Ibrahim I. Cisse; Robert G. Roeder; Phillip A. Sharp; Arup K. Chakraborty; Richard A. Young
• Keywords: Cell Nucleus; 0303 health sciences; 610; Nuclear Proteins; 510; Molecular Imaging; Intrinsically Disordered Proteins; Glycols; Mediator Complex Subunit 1; Mice; 03 medical and health sciences; Enhancer Elements, Genetic; HEK293 Cells; Gene Expression Regulation; NIH 3T3 Cells; Serine; Trans-Activators; Animals; Humans; Immunoprecipitation; Conserved Sequence; Embryonic Stem Cells; Fluorescence Recovery After Photobleaching; Transcription Factors

Phase separation and gene control

Many components of eukaryotic transcription machinery—such as transcription factors and cofactors including BRD4, subunits of the Mediator complex, and RNA polymerase II—contain intrinsically disordered low-complexity domains. Now a conceptual framework connecting the nature and behavior of their interactions to their functions in transcription regulation is emerging (see the Perspective by Plys and Kingston). Chong et al. found that low-complexity domains of transcription factors form concentrated hubs via functionally relevant dynamic, multivalent, and sequence-specific protein-protein interaction. These hubs have the potential to phase-separate at higher concentrations. Indeed, Sabari et al. showed that at super-enhancers, BRD4 and Mediator form liquid-like condensates that compartmentalize and concentrate the transcription apparatus to maintain expression of key cell-identity genes. Cho et al. further revealed the differential sensitivity of Mediator and RNA polymerase II condensates to selective transcription inhibitors and how their dynamic interactions might initiate transcription elongation.

Science , this issue p. eaar2555 , p. eaar3958 , p. 412 ; see also p. 329