Mediator and RNA polymerase II clusters associate in transcription-dependent condensates

By W. Cho, Jan-Hendrik Spille, Micca Hecht, Choongman Lee, Charles H. Li, Valentin Grube, I. Cissé. Science, 2018

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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 Critical components of transcription machinery form stable, condensate-like, transcription-dependent clusters in cells. Models of gene control have emerged from genetic and biochemical studies, with limited consideration of the spatial organization and dynamics of key components in living cells. We used live-cell superresolution and light-sheet imaging to study the organization and dynamics of the Mediator coactivator and RNA polymerase II (Pol II) directly. Mediator and Pol II each form small transient and large stable clusters in living embryonic stem cells. Mediator and Pol II are colocalized in the stable clusters, which associate with chromatin, have properties of phase-separated condensates, and are sensitive to transcriptional inhibitors. We suggest that large clusters of Mediator, recruited by transcription factors at large or clustered enhancer elements, interact with large Pol II clusters in transcriptional condensates in vivo.

Subfields: Biophysics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/a97172a063ec46879a6f6fad0fb824fe299919d6

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Citations in the corpus

Liquid-Liquid Phase Separation in Disease. (2019, background): “Indeed, a series of recent studies have raised the possibility that condensate formation is critical for regulation of transcription (21, 23, 32, 34, 70, 134).”
Organization of Chromatin by Intrinsic and Regulated Phase Separation (2019, background): “Multibromodomain proteins can induce a distinct droplet phase of acetylated chromatin, consistent with reports that transcriptional regulators recruited to acetylated enhancers form a phase separated structure important for gene expression (Boija et al., 2018; Cho et al., 2018; Sabari et al., 2018).”
Coactivator condensation at super-enhancers links phase separation and gene control (2018, background): “The model whereby phase separation of coactivators compartmentalizes and concentrates the transcription apparatus at SEs and their regulated genes, described here and corroborated by (57), raises many questions.”