Transcription factors activate genes through the phase separation capacity of their activation domains

By Ann Boija, Isaac A. Klein, Benjamin R. Sabari, Alessandra Dall’Agnese, Eliot L. Coffey, A. V. Zamudio, Charles H. Li, K. Shrinivas, John C. Manteiga, N. Hannett and 9 more. Cell, 2018

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Gene expression is controlled by transcription factors (TFs) that consist of DNA-binding domains (DBDs) and activation domains (ADs). The DBDs have been well-characterized, but little is known about the mechanisms by which ADs effect gene activation. Here we report that diverse ADs form phase-separated condensates with the Mediator coactivator. For the OCT4 and GCN4 TFs, we show that the ability to form phase-separated droplets with Mediator in vitro and the ability to activate genes in vivo are dependent on the same amino acid residues. For the estrogen receptor (ER), a ligand-dependent activator, we show that estrogen enhances phase separation with Mediator, again linking phase separation with gene activation. These results suggest that diverse TFs can interact with Mediator through the phase-separating capacity of their ADs and that formation of condensates with Mediator is involved in gene activation.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e4f0debfff8b369862f80cc3adec3518a77760c0

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Citations in the corpus

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).”
Proteolysis Targeting Chimeras as Therapeutics and Tools for Biological Discovery (2020, positive): “It has also been used to demonstrate that YY1 has no direct role in the modulation of replication timing (Sima et al., 2019) and to demonstrate that the OCT4 is crucial for the localization of Mediator condensates at super-enhancers in embryonic stem cells (Boija et al., 2018).”
Transcription factors interact with RNA to regulate genes (2022, background): “TFs also contain effector domains that exhibit less sequence conservation and sample many transient structures that enable multivalent protein interactions (Arnold et al., 2018; Boija et al., 2018; Soto et al., 2022).”
Liquid-Liquid Phase Separation in Disease. (2019, background): “In this framework, IDRs and IDPs can be described as polymers consisting of two fundamental units: stickers and spacers (152).”