Transcription Factors Activate Genes Through the Phase-Separation Capacity of Their Activation Domains

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2018 Nov 20

PMID 30449618

Citations 806

Authors

Ann Boija

Isaac A Klein

Benjamin R Sabari

Alessandra DallAgnese

Eliot L Coffey

Alicia V Zamudio

Charles H Li

Krishna Shrinivas

John C Manteiga

Nancy M Hannett

Brian J Abraham

Lena K Afeyan

Yang E Guo

Jenna K Rimel

Charli B Fant

Jurian Schuijers

Tong Ihn Lee

Dylan J Taatjes

Richard A Young

Affiliations

Soon will be listed here.

Abstract

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.

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References

Oliner J, Andresen J, Hansen S, Zhou S, Tjian R . SREBP transcriptional activity is mediated through an interaction with the CREB-binding protein. Genes Dev. 1996; 10(22):2903-11. DOI: 10.1101/gad.10.22.2903. View

Brent R, Ptashne M . A eukaryotic transcriptional activator bearing the DNA specificity of a prokaryotic repressor. Cell. 1985; 43(3 Pt 2):729-36. DOI: 10.1016/0092-8674(85)90246-6. View

Roberts S . Mechanisms of action of transcription activation and repression domains. Cell Mol Life Sci. 2000; 57(8-9):1149-60. PMC: 11147075. DOI: 10.1007/pl00000755. View

Habchi J, Tompa P, Longhi S, Uversky V . Introducing protein intrinsic disorder. Chem Rev. 2014; 114(13):6561-88. DOI: 10.1021/cr400514h. View

Patel A, Lee H, Jawerth L, Maharana S, Jahnel M, Hein M . A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation. Cell. 2015; 162(5):1066-77. DOI: 10.1016/j.cell.2015.07.047. View

Triezenberg S . Structure and function of transcriptional activation domains. Curr Opin Genet Dev. 1995; 5(2):190-6. DOI: 10.1016/0959-437x(95)80007-7. View

Staller M, Holehouse A, Swain-Lenz D, Das R, Pappu R, Cohen B . A High-Throughput Mutational Scan of an Intrinsically Disordered Acidic Transcriptional Activation Domain. Cell Syst. 2018; 6(4):444-455.e6. PMC: 5920710. DOI: 10.1016/j.cels.2018.01.015. View

Oates M, Romero P, Ishida T, Ghalwash M, Mizianty M, Xue B . D²P²: database of disordered protein predictions. Nucleic Acids Res. 2012; 41(Database issue):D508-16. PMC: 3531159. DOI: 10.1093/nar/gks1226. View

Holehouse A, Das R, Ahad J, Richardson M, Pappu R . CIDER: Resources to Analyze Sequence-Ensemble Relationships of Intrinsically Disordered Proteins. Biophys J. 2017; 112(1):16-21. PMC: 5232785. DOI: 10.1016/j.bpj.2016.11.3200. View

10.

Liu W, Coleman R, Ma E, Grob P, Yang J, Zhang Y . Structures of three distinct activator-TFIID complexes. Genes Dev. 2009; 23(13):1510-21. PMC: 2704470. DOI: 10.1101/gad.1790709. View

11.

Soutourina J . Transcription regulation by the Mediator complex. Nat Rev Mol Cell Biol. 2017; 19(4):262-274. DOI: 10.1038/nrm.2017.115. View

12.

Burke K, Janke A, Rhine C, Fawzi N . Residue-by-Residue View of In Vitro FUS Granules that Bind the C-Terminal Domain of RNA Polymerase II. Mol Cell. 2015; 60(2):231-41. PMC: 4609301. DOI: 10.1016/j.molcel.2015.09.006. View

13.

Fulton D, Sundararajan S, Badis G, Hughes T, Wasserman W, Roach J . TFCat: the curated catalog of mouse and human transcription factors. Genome Biol. 2009; 10(3):R29. PMC: 2691000. DOI: 10.1186/gb-2009-10-3-r29. View

14.

Nott T, Petsalaki E, Farber P, Jervis D, Fussner E, Plochowietz A . Phase transition of a disordered nuage protein generates environmentally responsive membraneless organelles. Mol Cell. 2015; 57(5):936-947. PMC: 4352761. DOI: 10.1016/j.molcel.2015.01.013. View

15.

Meyer K, Donner A, Knuesel M, York A, Espinosa J, Taatjes D . Cooperative activity of cdk8 and GCN5L within Mediator directs tandem phosphoacetylation of histone H3. EMBO J. 2008; 27(10):1447-57. PMC: 2396395. DOI: 10.1038/emboj.2008.78. View

16.

Weintraub A, Li C, Zamudio A, Sigova A, Hannett N, Day D . YY1 Is a Structural Regulator of Enhancer-Promoter Loops. Cell. 2017; 171(7):1573-1588.e28. PMC: 5785279. DOI: 10.1016/j.cell.2017.11.008. View

17.

Drysdale C, Duenas E, Jackson B, Reusser U, Braus G, Hinnebusch A . The transcriptional activator GCN4 contains multiple activation domains that are critically dependent on hydrophobic amino acids. Mol Cell Biol. 1995; 15(3):1220-33. PMC: 230345. DOI: 10.1128/MCB.15.3.1220. View

18.

Dunker A, Bondos S, Huang F, Oldfield C . Intrinsically disordered proteins and multicellular organisms. Semin Cell Dev Biol. 2014; 37:44-55. DOI: 10.1016/j.semcdb.2014.09.025. View

19.

Mitchell P, Tjian R . Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins. Science. 1989; 245(4916):371-8. DOI: 10.1126/science.2667136. View

20.

Frietze S, Farnham P . Transcription factor effector domains. Subcell Biochem. 2011; 52:261-77. PMC: 4151296. DOI: 10.1007/978-90-481-9069-0_12. View