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• W3092383985 abstract "Activating the right gene at the right time and place is essential for development. Emerging evidence suggests that this process is regulated by the mesoscale compartmentalization of the gene-control machinery, RNA polymerase II and its cofactors, within biomolecular condensates. Coupling gene activity to the reversible and dynamic process of condensate formation is proposed to enable the robust and precise changes in gene-regulatory programs during signaling and development. The macromolecular features that enable condensates and the regulatory pathways that control them are dysregulated in disease, highlighting their importance for normal physiology. In this review, we will discuss the role of condensates in gene activation; the multivalent features of protein, RNA, and DNA that enable reversible condensate formation; and how these processes are utilized in normal and disease biology. Understanding the regulation of condensates promises to provide novel insights into how organization of the gene-control machinery regulates development and disease. Activating the right gene at the right time and place is essential for development. Emerging evidence suggests that this process is regulated by the mesoscale compartmentalization of the gene-control machinery, RNA polymerase II and its cofactors, within biomolecular condensates. Coupling gene activity to the reversible and dynamic process of condensate formation is proposed to enable the robust and precise changes in gene-regulatory programs during signaling and development. The macromolecular features that enable condensates and the regulatory pathways that control them are dysregulated in disease, highlighting their importance for normal physiology. In this review, we will discuss the role of condensates in gene activation; the multivalent features of protein, RNA, and DNA that enable reversible condensate formation; and how these processes are utilized in normal and disease biology. Understanding the regulation of condensates promises to provide novel insights into how organization of the gene-control machinery regulates development and disease. The process of development is established by gene-regulatory networks, which determine body plan by controlling when and where specific genes are activated or repressed (Davidson, 2010Davidson E.H. Emerging properties of animal gene regulatory networks.Nature. 2010; 468: 911-920Crossref PubMed Scopus (332) Google Scholar). Through regulated readout of specific gene programs, a single genome can give rise to the large diversity of cellular phenotypes and functions found in multicellular organisms. Many processes play a role in gene regulation, and this review will focus on gene activation by recruitment of RNA Polymerase II (RNA Pol II) and its cofactors, which we will refer to collectively as the gene-control machinery. Hundreds of unique proteins and RNAs must work together at the correct genetic locus to ensure robust gene activation and must then be rapidly and precisely redistributed to activate new genes (Cramer, 2019Cramer P. Organization and regulation of gene transcription.Nature. 2019; 573: 45-54Crossref PubMed Scopus (29) Google Scholar; Roeder, 2019Roeder R.G. 50+ years of eukaryotic transcription: an expanding universe of factors and mechanisms.Nat. Struct. Mol. Biol. 2019; 26: 783-791Crossref PubMed Scopus (14) Google Scholar). In this context, activating new genes or gene programs during development requires the coordination of RNA Pol II and its hundreds of regulatory cofactors that must find one another at the right gene at the right time. This intricate choreography is performed within the highly crowded environment of the nucleus (Hancock and Jeon, 2014Hancock R. Jeon K.W. Preface. New models of the cell nucleus: crowding, entropic forces, phase separation, and fractals.Int. Rev. Cell Mol. Biol. 2014; 307: xiiiCrossref PubMed Scopus (7) Google Scholar). Given the large number of independent events required, local retention of the gene-control machinery at specific genomic loci would mitigate stochasticity and enable or accelerate the process of gene activation (Hancock and Jeon, 2014Hancock R. Jeon K.W. Preface. New models of the cell nucleus: crowding, entropic forces, phase separation, and fractals.Int. Rev. Cell Mol. Biol. 2014; 307: xiiiCrossref PubMed Scopus (7) Google Scholar; Lemon and Tjian, 2000Lemon B. Tjian R. Orchestrated response: a symphony of transcription factors for gene control.Genes Dev. 2000; 14: 2551-2569Crossref PubMed Scopus (0) Google Scholar; Matsuda et al., 2014Matsuda H. Putzel G.G. Backman V. Szleifer I. Macromolecular crowding as a regulator of gene transcription.Biophys. J. 2014; 106: 1801-1810Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar). Indeed, components of the gene-control machinery are found in dynamic clusters where many copies of individual factors are at high local concentrations (Boija et al., 2018Boija A. Klein I.A. Sabari B.R. Dall'Agnese A. Coffey E.L. Zamudio A.V. Li C.H. Shrinivas K. Manteiga J.C. Hannett N.M. et al.Transcription factors activate genes through the phase-separation capacity of their activation domains.Cell. 2018; 175: 1842-1855.e16Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar; Cho et al., 2016Cho W.K. Jayanth N. English B.P. Inoue T. Andrews J.O. Conway W. Grimm J.B. Spille J.H. Lavis L.D. Lionnet T. Cisse I.I. RNA polymerase II cluster dynamics predict mRNA output in living cells.eLife. 2016; 5: 1123Crossref Scopus (75) Google Scholar, Cho et al., 2018Cho W.K. Spille J.H. Hecht M. 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Dense bicoid hubs accentuate binding along the morphogen gradient.Genes Dev. 2017; 31: 1784-1794Crossref PubMed Scopus (44) Google Scholar, Mir et al., 2018Mir M. Stadler M.R. Ortiz S.A. Hannon C.E. Harrison M.M. Darzacq X. Eisen M.B. Dynamic multifactor hubs interact transiently with sites of active transcription in Drosophila embryos.eLife. 2018; 7: e40497Crossref PubMed Scopus (23) Google Scholar; Papantonis and Cook, 2013Papantonis A. Cook P.R. Transcription factories: genome organization and gene regulation.Chem. Rev. 2013; 113: 8683-8705Crossref PubMed Scopus (112) Google Scholar; Sabari et al., 2018Sabari B.R. Dall'Agnese A. Boija A. Klein I.A. Coffey E.L. Shrinivas K. Abraham B.J. Hannett N.M. Zamudio A.V. Manteiga J.C. et al.Coactivator condensation at super-enhancers links phase separation and gene control.Science. 2018; 361: eaar3958Crossref PubMed Google Scholar; Tantale et al., 2016Tantale K. Mueller F. Kozulic-Pirher A. Lesne A. Victor J.M. Robert M.C. Capozi S. Chouaib R. Bäcker V. Mateos-Langerak J. et al.A single-molecule view of transcription reveals convoys of RNA polymerases and multi-scale bursting.Nat. Commun. 2016; 7: 12248Crossref PubMed Google Scholar; Tsai et al., 2017Tsai A. Muthusamy A.K. Alves M.R. Lavis L.D. Singer R.H. Stern D.L. Crocker J. Nuclear microenvironments modulate transcription from low-affinity enhancers.eLife. 2017; 6: e28975Crossref PubMed Scopus (34) Google Scholar). The exact nature of these clusters is not yet fully resolved, but it is generally agreed that constituents are concentrated because they engage in weak multivalent interactions with a dynamic nuclear substructure (Woringer and Darzacq, 2018Woringer M. Darzacq X. Protein motion in the nucleus: from anomalous diffusion to weak interactions.Biochemical Society Transactions. 2018; 46: 945-956Crossref PubMed Scopus (0) Google Scholar). Emerging evidence supports a model where the gene-control machinery is locally concentrated by compartmentalization within dynamic biomolecular condensates. Multivalent interactions among polymers produce networks that can yield phase separation once the attractive force of the interacting polymers becomes stronger than their interaction with the solvent (Flory, 1942Flory P.J. Thermodynamics of high polymer solutions.J. Chem. Phys. 1942; 10: 51-61Crossref Google Scholar; Semenov and Rubinstein, 1998Semenov A.N. Rubinstein M. Thermoreversible gelation in solutions of associative polymers. 1.Statics Macromolecules. 1998; 31: 1373-1385Crossref Google Scholar). Phase transitions occur across sharp thresholds and are often reversible. These concepts were proposed to underlie cellular organization over a century ago (Wilson, 1899Wilson E.B. The structure of protoplasm.Science. 1899; 10: 33-45Crossref PubMed Scopus (44) Google Scholar) and have recently been reinvigorated and expanded as a framework to study the numerous membraneless organelles, intracellular bodies, and other localized concentrations of functionally related macromolecules collectively referred to as biomolecular condensates (Banani et al., 2017Banani S.F. Lee H.O. Hyman A.A. Rosen M.K. Biomolecular condensates: organizers of cellular biochemistry.Nat. Rev. Mol. Cell Biol. 2017; 18: 285-298Crossref PubMed Scopus (834) Google Scholar; Brangwynne et al., 2009Brangwynne C.P. Eckmann C.R. Courson D.S. Rybarska A. Hoege C. Gharakhani J. Jülicher F. Hyman A.A. Germline P granules are liquid droplets that localize by controlled dissolution/condensation.Science. 2009; 324: 1729-1732Crossref PubMed Scopus (852) Google Scholar; Choi et al., 2020Choi J.M. Holehouse A.S. Pappu R.V. Physical principles underlying the complex biology of intracellular phase transitions.Annu. Rev. Biophys. 2020; 49: 107-133Crossref PubMed Scopus (23) Google Scholar; Hyman et al., 2014Hyman A.A. Weber C.A. Jülicher F. Liquid-liquid phase separation in biology.Annu. Rev. Cell Dev. Biol. 2014; 30: 39-58Crossref PubMed Google Scholar; Shin and Brangwynne, 2017Shin Y. Brangwynne C.P. Liquid phase condensation in cell physiology and disease.Science. 2017; 357: eaaf4382Crossref PubMed Scopus (559) Google Scholar). The term biomolecular condensate is used to describe a concentration of biomolecules irrespective of the specific physical and chemical mechanism leading to its formation (Banani et al., 2017Banani S.F. Lee H.O. Hyman A.A. Rosen M.K. Biomolecular condensates: organizers of cellular biochemistry.Nat. Rev. Mol. Cell Biol. 2017; 18: 285-298Crossref PubMed Scopus (834) Google Scholar). While the phase separation of a single polymer in solution is well understood and has been shown to underlie the formation of macromolecular droplets in vitro and condensates in cells, the complex, heterogeneous, and nonequilibrium environment of the cell should be expected to cause deviations in the predictions of these formalisms (Choi et al., 2019Choi J.M. Dar F. Pappu R.V. LASSI: a lattice model for simulating phase transitions of multivalent proteins.PLoS Comput. Biol. 2019; 15: e1007028Crossref PubMed Scopus (21) Google Scholar; McSwiggen et al., 2019McSwiggen D.T. Mir M. Darzacq X. Tjian R. Evaluating phase separation in live cells: diagnosis, caveats, and functional consequences.Genes Dev. 2019; 33: 1619-1634Crossref PubMed Scopus (29) Google Scholar; Riback et al., 2020Riback J.A. Zhu L. Ferrolino M.C. Tolbert M. Mitrea D.M. Sanders D.W. Wei M.-T. Kriwacki R.W. Brangwynne C.P. Composition-dependent thermodynamics of intracellular phase separation.Nature. 2020; 581: 209-214Crossref PubMed Scopus (0) Google Scholar). Nevertheless, when applied to biological systems, these concepts have led to numerous advances and breakthroughs related to the cellular organization of essential biological processes (see other reviews in this issue). Many nuclear processes are compartmentalized within condensates (Sabari et al., 2020Sabari B.R. Dall'Agnese A. Young R.A. Biomolecular condensates in the nucleus.Trends Biochem. Sci. 2020; https://doi.org/10.1016/j.tibs.2020.06.007Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar; Strom and Brangwynne, 2019Strom A.R. Brangwynne C.P. The liquid nucleome - phase transitions in the nucleus at a glance.J. Cell Sci. 2019; 132: jcs235093Crossref PubMed Scopus (0) Google Scholar; Zhu and Brangwynne, 2015Zhu L. Brangwynne C.P. Nuclear bodies: the emerging biophysics of nucleoplasmic phases.Curr. Opin. Cell Biol. 2015; 34: 23-30Crossref PubMed Scopus (135) Google Scholar). Here, we focus on an emerging role for condensates in regulating the initiation and activation of gene transcription, how this process is used during development to switch between gene expression programs, and how it is dysregulated in disease. Formation of on-demand and reversible local concentrations of functionally related proteins at specific enhancers and promoters is an attractive model for how cells respond to signals and how cell-state transitions are accomplished. Coupling the activation of genes to the formation of condensates would allow for precise and nonlinear changes in gene-expression programs in response to signaling and during development. We will first discuss how condensates influence gene activation followed by a review of the multivalent features of the gene-control machinery and specific genomic loci, which together enable formation of condensates. We will then focus on how these multivalent interactions are regulated to reposition condensates to new targets during development and how this process is dysregulated in disease. We will close by highlighting a few of the many open areas for future work. Gene activation is a multicomponent and multistep biochemical process that must occur at specific genomic loci. This is analogous to the multicomponent and multistep biochemical assembly of signaling clusters at the plasma membrane, where diffusion away from the site of signaling is mitigated by local retention of reactants within a condensate, leading to increased specific activity of the pathway (Case et al., 2019bCase L.B. Zhang X. Ditlev J.A. Rosen M.K. Stoichiometry controls activity of phase-separated clusters of actin signaling proteins.Science. 2019; 363: 1093-1097Crossref PubMed Scopus (4) Google Scholar; Huang et al., 2019Huang W.Y.C. Alvarez S. Kondo Y. Lee Y.K. Chung J.K. Lam H.Y.M. Biswas K.H. Kuriyan J. Groves J.T. A molecular assembly phase transition and kinetic proofreading modulate Ras activation by SOS.Science. 2019; 363: 1098-1103Crossref PubMed Scopus (31) Google Scholar). Similarly, components of the gene-control machinery are locally retained at sites of gene activity (Cho et al., 2016Cho W.K. Jayanth N. English B.P. Inoue T. Andrews J.O. Conway W. Grimm J.B. Spille J.H. Lavis L.D. Lionnet T. Cisse I.I. RNA polymerase II cluster dynamics predict mRNA output in living cells.eLife. 2016; 5: 1123Crossref Scopus (75) Google Scholar; Li et al., 2019Li J. Dong A. Saydaminova K. Chang H. Wang G. Ochiai H. Yamamoto T. Pertsinidis A. Single-molecule nanoscopy elucidates RNA polymerase II transcription at single genes in live cells.Cell. 2019; 178: 491-506.e28Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar; Mir et al., 2018Mir M. Stadler M.R. Ortiz S.A. Hannon C.E. Harrison M.M. Darzacq X. Eisen M.B. Dynamic multifactor hubs interact transiently with sites of active transcription in Drosophila embryos.eLife. 2018; 7: e40497Crossref PubMed Scopus (23) Google Scholar). These high local concentrations have functional outcomes for gene expression, as the number of RNA Pol II molecules locally concentrated is positively correlated with the number of transcribed RNA molecules (Cho et al., 2016Cho W.K. Jayanth N. English B.P. Inoue T. Andrews J.O. Conway W. Grimm J.B. Spille J.H. Lavis L.D. Lionnet T. Cisse I.I. RNA polymerase II cluster dynamics predict mRNA output in living cells.eLife. 2016; 5: 1123Crossref Scopus (75) Google Scholar) and preventing clustering of the gene-control machinery leads to reduced gene expression (Li et al., 2019Li J. Dong A. Saydaminova K. Chang H. Wang G. Ochiai H. Yamamoto T. Pertsinidis A. Single-molecule nanoscopy elucidates RNA polymerase II transcription at single genes in live cells.Cell. 2019; 178: 491-506.e28Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). These high local concentrations can be attributed to RNA Pol II and its cofactors engaging in dynamic multivalent interactions with themselves and other components of condensates formed at specific genomic loci. Condensates composed of coactivator protein formed in cell-free nuclear extracts partition RNA Pol II and other cofactors (Sabari et al., 2018Sabari B.R. Dall'Agnese A. Boija A. Klein I.A. Coffey E.L. Shrinivas K. Abraham B.J. Hannett N.M. Zamudio A.V. Manteiga J.C. et al.Coactivator condensation at super-enhancers links phase separation and gene control.Science. 2018; 361: eaar3958Crossref PubMed Google Scholar). The degree to which TAF15 hydrogels partition the low-complexity C-terminal domain (CTD) of RNA Pol II in vitro positively correlates with the ability of that protein to activate transcription of a reporter gene in cells (Kwon et al., 2013Kwon I. Kato M. Xiang S. Wu L. Theodoropoulos P. Mirzaei H. Han T. Xie S. Corden J.L. McKnight S.L. Phosphorylation-regulated binding of RNA polymerase II to fibrous polymers of low-complexity domains.Cell. 2013; 155: 1049-1060Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar). RNA Pol II condensate formation in vitro and clustering in cell nuclei are dependent on the length of the CTD (Boehning et al., 2018Boehning M. Dugast-Darzacq C. Rankovic M. Hansen A.S. Yu T. Marie-Nelly H. McSwiggen D.T. Kokic G. Dailey G.M. Cramer P. et al.RNA polymerase II clustering through carboxy-terminal domain phase separation.Nat. Struct. Mol. Biol. 2018; 25: 833-840Crossref PubMed Scopus (97) Google Scholar), indicating that the enzyme’s ability to cluster relies on the dynamic multivalent interactions modeled in vitro. In cells, synthetic condensates formed by light-induced clustering of defined protein domains compartmentalize RNA Pol II and locally enhance RNA synthesis (Wei et al., 2020Wei M.-T. Chang Y.-C. Shimobayashi S.F. Shin Y. Strom A.R. Brangwynne C.P. Nucleated transcriptional condensates amplify gene expression.Nat Cell Biol. 2020; https://doi.org/10.1038/s41556-020-00578-6Crossref Scopus (0) Google Scholar). Intriguingly, while all protein domains tested formed light-induced condensates, only some were capable of enhancing transcription (Wei et al., 2020Wei M.-T. Chang Y.-C. Shimobayashi S.F. Shin Y. Strom A.R. Brangwynne C.P. Nucleated transcriptional condensates amplify gene expression.Nat Cell Biol. 2020; https://doi.org/10.1038/s41556-020-00578-6Crossref Scopus (0) Google Scholar), highlighting the importance of condensate composition on function. These and other studies provide evidence that compartmentalization of the gene-control machinery within condensates promotes transcription of associated genes. Based on these and other studies, a picture of how condensates can influence gene activation is taking shape, whereby macromolecules capable of engaging in multivalent interactions are clustered together at specific genomic loci where they concentrate RNA Pol II and its many cofactors (Figure 1). This model predicts that the extent and frequency with which a locus can concentrate RNA Pol II and cofactor molecules will influence gene-expression output. This regulation by organization does not supersede the regulatory mechanisms described for RNA Pol II recruitment and activity (Cramer, 2019Cramer P. Organization and regulation of gene transcription.Nature. 2019; 573: 45-54Crossref PubMed Scopus (29) Google Scholar; Roeder, 2019Roeder R.G. 50+ years of eukaryotic transcription: an expanding universe of factors and mechanisms.Nat. Struct. Mol. Biol. 2019; 26: 783-791Crossref PubMed Scopus (14) Google Scholar) but is a means to regulate whether involved factors do or do not find one another in the crowded environment of the nucleus. Additionally, the requirement for clustering of many factors together to ensure high transcriptional activity has the potential to reduce noise at sites of the genome less capable of promoting condensate formation, a feature that has also been proposed for signaling clusters (Case et al., 2019aCase L.B. Ditlev J.A. Rosen M.K. Regulation of transmembrane signaling by phase separation.Annu. Rev. Biophys. 2019; 48: 465-494Crossref PubMed Scopus (20) Google Scholar). This ability to robustly activate specific genes while maintaining other sites unexpressed is particularly desirable during cell-state transitions and in maintaining cell identity. This additional layer of regulation provided by condensates is mediated by dynamic multivalent interactions inherent to the gene-control machinery. The spatial organization of the gene-control machinery by highly dynamic and multivalent interactions has long been noted (Fuxreiter et al., 2008Fuxreiter M. Tompa P. Simon I. Uversky V.N. Hansen J.C. Asturias F.J. Malleable machines take shape in eukaryotic transcriptional regulation.Nat. Chem. Biol. 2008; 4: 728-737Crossref PubMed Scopus (148) Google Scholar; Kaiser et al., 2008Kaiser T.E. Intine R.V. Dundr M. De novo formation of a subnuclear body.Science. 2008; 322: 1713-1717Crossref PubMed Scopus (167) Google Scholar; Mao et al., 2011Mao Y.S. Zhang B. Spector D.L. 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DNA-binding transcription factors (TFs), transcriptional coactivators, regulatory enzymes, chromatin-associated cofactors, and RNA Pol II are capable of engaging in multivalent interactions with one another and with specific regions of the genome (Boehning et al., 2018Boehning M. Dugast-Darzacq C. Rankovic M. Hansen A.S. Yu T. Marie-Nelly H. McSwiggen D.T. Kokic G. Dailey G.M. Cramer P. et al.RNA polymerase II clustering through carboxy-terminal domain phase separation.Nat. Struct. Mol. Biol. 2018; 25: 833-840Crossref PubMed Scopus (97) Google Scholar; Boija et al., 2018Boija A. Klein I.A. Sabari B.R. Dall'Agnese A. Coffey E.L. Zamudio A.V. Li C.H. Shrinivas K. Manteiga J.C. Hannett N.M. et al.Transcription factors activate genes through the phase-separation capacity of their activation domains.Cell. 2018; 175: 1842-1855.e16Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar; Kwon et al., 2013Kwon I. Kato M. Xiang S. Wu L. Theodoropoulos P. Mirzaei H. Han T. Xie S. 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Together, these two layers can coordinate the establishment of condensates at specific genomic loci and determine the composition of concentrated components (Figure 2C). Modulating the interactions at either tier can change when and where condensates will form and with which components. The chromatin fiber has many layers of regulated interactions that can reversibly tune the type and number of interactions at specific regions (Figure 2A). The compaction of the chromatin fiber into various chromatin-rich condensates (Gibson et al., 2019Gibson B.A. Doolittle L.K. Schneider M.W.G. Jensen L.E. Gamarra N. Henry L. Gerlich D.W. Redding S. Rosen M.K. Organization of chromatin by intrinsic and regulated phase separation.Cell. 2019; 179: 470-484.e21Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar; Larson et al., 2017Larson A.G. Elnatan D. Keenen M.M. Trnka M.J. Johnston J.B. Burlingame A.L. Agard D.A. Redding S. Narlikar G.J. 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Chromatin-rich condensates can be dissolved by the regulation of nucleosome spacing and reversible acetylation of histone proteins (Gibson et al., 2019Gibson B.A. Doolittle L.K. Schneider M.W.G. Jensen L.E. Gamarra N. Henry L. Gerlich D.W. Redding S. Rosen M.K. Organization of chromatin by intrinsic and regulated phase separation.Cell. 2019; 179: 470-484.e21Abstract Fu" @default.
• W3092383985 created "2020-10-15" @default.
• W3092383985 creator A5064694236 @default.
• W3092383985 date "2020-10-01" @default.
• W3092383985 modified "2023-10-14" @default.
• W3092383985 title "Biomolecular Condensates and Gene Activation in Development and Disease" @default.
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