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• W2904362005 abstract "New findings suggest that transcription enhancers work by recruitment of a large dynamic network of coactivators and other factors responsible for gene activation. Formation of these condensates is driven by DNA-bound transcription factors, their intrinsically disordered activation domains, and dynamic low-specificity interactions within the complex. New findings suggest that transcription enhancers work by recruitment of a large dynamic network of coactivators and other factors responsible for gene activation. Formation of these condensates is driven by DNA-bound transcription factors, their intrinsically disordered activation domains, and dynamic low-specificity interactions within the complex. The mechanism of transcriptional regulation by enhancers has been difficult to understand. Transcription factors binding to these elements somehow regulate transcription initiation and subsequent events many thousands of base pairs distant from target genes. Adding to this confusion, the activation domains contained within these enhancer-binding factors are intrinsically disordered, contain no common conserved amino acid sequence motifs, and often bind their target proteins with relatively low affinity and specificity. How can such weak low-specificity interactions combine to precisely regulate patterns of gene expression that direct complex processes such as development, growth regulation, and stress response? Over the past few years, there has been an explosion of discoveries at the molecular level concerning how intrinsically disordered proteins function in molecular recognition and how they contribute to enhancer function by promoting dynamic cellular condensates. Several very recent papers (Cho et al., 2018Cho W.-K. Spille J.-H. Hecht M. Lee C. Li C. Grube V. Cisse I.I. Mediator and RNA polymerase II clusters associate in transcription-dependent condensates.Science. 2018; 361: 412-415Crossref PubMed Scopus (612) Google Scholar, Chong et al., 2018Chong S. Dugast-Darzacq C. Liu Z. Dong P. Dailey G.M. Cattoglio C. Heckert A. Banala S. Lavis L. Darzacq X. et al.Imaging dynamic and selective low-complexity domain interactions that control gene transcription.Science. 2018; 361Crossref Scopus (473) 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; 361Crossref PubMed Google Scholar), including one from the Young lab in this issue of Cell (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 (this issue): 1842-1855Abstract Full Text Full Text PDF PubMed Scopus (707) Google Scholar), have led to a new paradigm for enhancer function in which enhancers recruit and concentrate large numbers of transcription factors, coactivators, and at least some components of the basal transcription machinery into dynamic complexes. This compartmentalization mechanism turns the weak and low-specificity properties of intrinsically disordered proteins into a strength, effectively increasing the specificity of interactions while retaining the dynamic nature of the complex. The work on the role of cellular condensates in enhancer function began with the goal of understanding how super enhancers function. In contrast to the many thousands of typical cellular enhancers that are usually a few hundred base pairs in length, cells contain several hundred cell-type-specific super enhancers (Whyte et al., 2013Whyte W.A. Orlando D.A. Hnisz D. Abraham B.J. Lin C.Y. Kagey M.H. Rahl P.B. Lee T.I. Young R.A. Master transcription factors and mediator establish super-enhancers at key cell identity genes.Cell. 2013; 153: 307-319Abstract Full Text Full Text PDF PubMed Scopus (2289) Google Scholar), which contain large clusters of transcription-factor binding sites that span tens of thousands of base pairs. Super enhancers drive expression of genes that define cell identity and nucleate a high density of colocalized factors such as the coactivator Mediator, RNA polymerase II (Pol II), and other factors responsible for gene activation and chromatin architecture. Based on these and other properties, it has been proposed that super enhancers promote liquid-liquid phase transition, a widely used mechanism to form non-membrane-bound compartments and reversibly organize molecules within cells (Hnisz et al., 2017Hnisz D. Shrinivas K. Young R.A. Chakraborty A.K. Sharp P.A. A Phase Separation Model for Transcriptional Control.Cell. 2017; 169: 13-23Abstract Full Text Full Text PDF PubMed Scopus (866) Google Scholar). Many phase-separated compartments show liquid-like characteristics such as round shape, dynamic internal components, and the ability to flow, drip, and fuse. Formation of these condensates, in which the components are concentrated relative to the surroundings, is driven by weak and dynamic multivalent interactions. This model potentially explains an important role for intrinsic disorder, a feature of key proteins within liquid-like compartments, the basis for cooperativity of transcription factors in the activity of a typical enhancer, and the ability of a single enhancer to simultaneously activate two linked genes. In a first direct test of this model, the Cisse and Young groups used advanced live-cell imaging methods to detect cellular condensates associated with several super-enhancer-controlled genes that contain Mediator, Pol II and the super-enhancer-binding transcription factor Brd4 (Cho et al., 2018Cho W.-K. Spille J.-H. Hecht M. Lee C. Li C. Grube V. Cisse I.I. Mediator and RNA polymerase II clusters associate in transcription-dependent condensates.Science. 2018; 361: 412-415Crossref PubMed Scopus (612) 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; 361Crossref PubMed Google Scholar). The condensates were shown to occur at sites of active transcription, a known property of active enhancers. Intrinsically disordered proteins often contain low-amino-acid-sequence complexity domains that have a tendency to phase separate. Consistent with the phase separation model, the intrinsically disordered regions of both Med1 (a Mediator subunit) and Brd4 form liquid droplets in vitro. In the present work, Boija et al. show that the transcription factor Oct4, another key component of mouse embryonic stem cell super enhancers, is also localized within the super enhancer condensates and that these dissolve upon depletion of Oct4 protein. In a series of in vitro experiments, the propensity of Med1 and eight mammalian TFs for droplet formation is assessed. Many of the transcription factors form droplets on their own and all are incorporated into droplets along with Med1 when mixed. This property also extends to the yeast system where the tandem activation domains from the transcription factor Gcn4 and the Mediator subunit Med15 form mixed droplets. In some of the above cases, heavily mutated activation domains lose the ability to form droplets, concurrent with loss of transcription activation function, although derivatives with fewer total mutations will be necessary to establish if these two properties are interdependent. In an independent study (Chong et al., 2018Chong S. Dugast-Darzacq C. Liu Z. Dong P. Dailey G.M. Cattoglio C. Heckert A. Banala S. Lavis L. Darzacq X. et al.Imaging dynamic and selective low-complexity domain interactions that control gene transcription.Science. 2018; 361Crossref Scopus (473) Google Scholar), the Tjian and Darzaq groups use live-cell imaging to examine the in vivo interactions of two distinct transcription-factor low-complexity domains: the FET family (FUS, EWS, and TAF15) and Sp1. Upon recruitment of DNA binding domain-low-complexity domain fusions to large artificial arrays and natural microsatellite repeats, they observe phase-separated condensates that are termed “interaction hubs” in which the resident transcription factors are in significant excess over the number of binding sites. These hubs recruit Pol II and show dynamic behavior with residence times on the order of seconds. The interactions between low-complexity domains exhibit specificity, as those from the FET family, but not from Sp1, could colocalize. Finally, one heavily mutated low-complexity domain loses both the ability to efficiently form hubs and to activate transcription. While these studies were not designed to probe the structure and physical nature of the hubs, liquid-like properties including spherical shape and local changes in refractive index are not observed. While more work will be required to address the question of liquid-like properties in all the phase-separated systems discussed above, it is clear that droplet formation is sensitive to protein concentration and other variables so that liquid droplet formation in vitro does not necessarily translate to droplet formation in vivo. Focusing on this question, however, is missing the larger picture: that enhancers and their resident transcription factors recruit a large mass of factors required for gene activation in a dynamic complex. This is a new way of thinking about enhancer function compared to the old models where one enhancer targeted one promoter via a single coactivator, such as Mediator. Much recent work on molecular recognition mechanisms used by intrinsically disordered proteins fits nicely with these results and potentially explains why they are key components of the condensates. For example, the tandem activation domains from Gcn4 use a dynamic fuzzy binding mechanism to target four activator-binding domains on the Mediator subunit Med15 (Tuttle et al., 2018Tuttle L.M. Pacheco D. Warfield L. Luo J. Ranish J. Hahn S. Klevit R.E. Gcn4-Mediator Specificity Is Mediated by a Large and Dynamic Fuzzy Protein-Protein Complex.Cell Rep. 2018; 22: 3251-3264Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). Fuzzy binding is a widely used mechanism in recognition by intrinsically disordered proteins in which there is no unique protein-protein interface in the bound state, with rapid conformational exchange between different binding modes (Fuxreiter, 2018Fuxreiter M. Fuzziness in Protein Interactions-A Historical Perspective.J. Mol. Biol. 2018; 430: 2278-2287Crossref PubMed Scopus (97) Google Scholar). In the case of Gcn4-Med15, the individual activation domains appear to interact with individual activator binding domains via a cloud of hydrophobicity rather than sequence-specific interactions (Tuttle et al., 2018Tuttle L.M. Pacheco D. Warfield L. Luo J. Ranish J. Hahn S. Klevit R.E. Gcn4-Mediator Specificity Is Mediated by a Large and Dynamic Fuzzy Protein-Protein Complex.Cell Rep. 2018; 22: 3251-3264Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). Such a dynamic binding mechanism can easily be scaled so that one transcription factor can simultaneously recruit multiple copies of one or more coactivators and other binding partners, potentially explaining how a large number of molecules are found in condensates compared to the number of transcription-factor binding sites (Figure 1). These new findings, while explaining the nature of large super-enhancers, raise the question of whether typical enhancers also work by this mechanism, but on a smaller scale. This may be challenging to address by current imaging methods due to the abundance of cellular enhancers and the relatively smaller number of factors at each typical enhancer. Second, what is the biological function of the condensates? Does the high concentration of factors at an enhancer make the search for its target promoters more efficient, increase specificity of the interactions by compartmentalization, or work by other mechanisms? Third, what are the components of the condensates? Phase-shifted bodies such as stress granules contain hundreds of different proteins, so it will be important to characterize these enhancer complexes in order to understand their function. Typical condensates contain a few key proteins essential for droplet formation that recruit other components (Ditlev et al., 2018Ditlev J.A. Case L.B. Rosen M.K. Who’s In and Who’s Out-Compositional Control of Biomolecular Condensates.J. Mol. Biol. 2018; 430: 4666-4684Crossref PubMed Scopus (149) Google Scholar). So far, nearly all tested components of the super-enhancer condensates are important for condensate formation (Mediator, Brd4, and Oct4, but not Pol II). Fourth, what are the properties of activation domains that promote formation of these dynamic complexes? For example, what sequences can function as activation domains, what is their biochemical specificity, and what combinations of them can function together to generate an active enhancer? Combined with the exciting new studies, answers to these and other questions raised by this new work will pull back the curtain on the longstanding mysteries of enhancer function and how they orchestrate complex patterns of gene control leading to the great diversity of complex organisms. S.H. is supported by NIH grant RO1 GM075114. Transcription Factors Activate Genes through the Phase-Separation Capacity of Their Activation DomainsBoija et al.CellNovember 15, 2018In BriefActivation domains from a diverse array of mammalian and yeast transcription factors form phase-separated condensates with Mediator to activate gene expression. Full-Text PDF Open Archive" @default.
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• W2904362005 title "Phase Separation, Protein Disorder, and Enhancer Function" @default.
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