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The Mediator complex: a central integrator of transcription

Key Points

  • A basic function of the Mediator complex is to communicate regulatory signals from DNA-binding transcription factors (TFs) directly to RNA polymerase II (Pol II).

  • Different TFs, and the signalling pathways that regulate these TFs, often interact with different Mediator subunits to regulate expression of their target genes.

  • Mediator is composed of a large number of subunits, some of which can reversibly associate with Mediator or are expressed at variable levels in different cell types.

  • Mediator binding to various proteins and protein complexes, such as TFs, Pol II and the cyclin-dependent kinase 8 (CDK8) module, results in large-scale structural changes. These structural changes, in turn, appear to modulate the function of Mediator and may affect its ability to bind to other proteins.

  • Because of its direct and extensive interactions with Pol II, Mediator regulates multiple stages of Pol II transcription (for example, initiation and re-initiation). Mediator interactions with the super elongation complex (SEC) also seem to be important for its regulation of Pol II elongation.

  • The interactions between TFs, Mediator, cohesin and the pre-initiation complex (PIC) correlate with the formation of enhancer–promoter DNA loops, which are an important regulatory mechanism. Interactions between Mediator and non-coding RNA also correlate with DNA looping.

Abstract

The RNA polymerase II (Pol II) enzyme transcribes all protein-coding and most non-coding RNA genes and is globally regulated by Mediator — a large, conformationally flexible protein complex with a variable subunit composition (for example, a four-subunit cyclin-dependent kinase 8 module can reversibly associate with it). These biochemical characteristics are fundamentally important for Mediator's ability to control various processes that are important for transcription, including the organization of chromatin architecture and the regulation of Pol II pre-initiation, initiation, re-initiation, pausing and elongation. Although Mediator exists in all eukaryotes, a variety of Mediator functions seem to be specific to metazoans, which is indicative of more diverse regulatory requirements.

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Figure 1: Structural changes in Mediator control its interactions with other transcription regulators.
Figure 2: A simplified model for Mediator-dependent regulation of multiple stages of RNA polymerase II transcription.
Figure 3: Mediator regulates chromatin architecture.
Figure 4: Mediator as an end point of signalling cascades.

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References

  1. Plank, J. L. & Dean, A. Enhancer function: mechanistic and genome-wide insights come together. Mol. Cell 55, 5–14 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Poss, Z. C., Ebmeier, C. C. & Taatjes, D. J. The Mediator complex and transcription regulation. Crit. Rev. Biochem. Mol. Biol. 48, 575–608 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ansari, S. A. & Morse, R. H. Mechanisms of Mediator complex action in transcriptional activation. Cell. Mol. Life Sci. 70, 2743–2756 (2013).

    Article  CAS  PubMed  Google Scholar 

  4. Xu, W. & Ji, J. Y. Dysregulation of CDK8 and Cyclin C in tumorigenesis. J. Genet. Genom. 38, 439–452 (2011).

    Article  CAS  Google Scholar 

  5. Spaeth, J. M., Kim, N. H. & Boyer, T. G. Mediator and human disease. Semin. Cell Dev. Biol. 22, 776–787 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Schiano, C., Casamassimi, A., Vietri, M. T., Rienzo, M. & Napoli, C. The roles of mediator complex in cardiovascular diseases. Biochim. Biophys. Acta 1839, 444–451 (2014).

    Article  CAS  PubMed  Google Scholar 

  7. Kulak, N. A., Pichler, G., Paron, I., Nagaraj, N. & Mann, M. Minimal, encapsulated proteomic-sample processing applied to copy-number estimation in eukaryotic cells. Nature Methods 11, 319–324 (2014).

    Article  CAS  PubMed  Google Scholar 

  8. Malik, S. et al. Structural and functional organization of TRAP220, the TRAP/mediator subunit that is targeted by nuclear receptors. Mol. Cell. Biol. 24, 8244–8254 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Taatjes, D. J. & Tjian, R. Structure and function of CRSP/Med2: a promoter-selective transcriptional co-activator complex. Mol. Cell 14, 675–683 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Fondell, J. D., Ge, H. & Roeder, R. G. Ligand induction of a transcriptionally active thyroid hormone receptor coactivator complex. Proc. Natl Acad. Sci. USA 93, 8329–8333 (1996). This paper reports the first biochemical purification of a human Mediator complex.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Stevens, J. L. et al. Transcription control by E1A and MAP kinase pathway via Sur2 mediator subunit. Science 296, 755–758 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Ito, M., Yuan, C. X., Okano, H. J., Darnell, R. B. & Roeder, R. G. Involvement of the TRAP220 component of the TRAP/SMCC coactivator complex in embryonic development and thyroid hormone action. Mol. Cell 5, 683–693 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. D'Alessio, J. A., Ng, R., Willenbring, H. & Tjian, R. Core promoter recognition complex changes accompany liver development. Proc. Natl Acad. Sci. USA 108, 3906–3911 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Deato, M. D. E. et al. MyoD targets TAF3/TRF3 to activate Myogenin transcription. Mol. Cell 32, 96–105 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Herrera, F. J., Yamaguchi, T., Roelink, H. & Tjian, R. Core promoter factor TAF9B regulates neuronal gene expression. Elife 3, e02559 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Liu, Y., Ranish, J. A., Aebersold, R. & Hahn, S. Yeast nuclear extract contains two major forms of RNA polymerase II mediator complexes. J. Biol. Chem. 276, 7169–7175 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Taatjes, D. J., Naar, A. M., Andel, F., Nogales, E. & Tjian, R. Structure, function, and activator-induced conformations of the CRSP coactivator. Science 295, 1058–1062 (2002). This study shows that the structural state of human Mediator changes upon binding to the activation domains of TFs.

    Article  CAS  PubMed  Google Scholar 

  18. Knuesel, M. T., Meyer, K. D., Bernecky, C. & Taatjes, D. J. The human CDK8 subcomplex is a molecular switch that controls Mediator co-activator function. Genes Dev. 23, 439–451 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Tsai, K. L. et al. A conserved Mediator–CDK8 kinase module association regulates Mediator–RNA polymerase II interaction. Nature Struct. Mol. Biol. 20, 611–619 (2013).

    Article  CAS  Google Scholar 

  20. Davis, M. A. et al. The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator. Genes Dev. 27, 151–156 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Barbieri, C. E. et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nature Genet. 44, 685–689 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Li, N. et al. Cyclin C is a haploinsufficient tumour suppressor. Nature Cell Biol. 16, 1080–1091 (2014).

    Article  CAS  PubMed  Google Scholar 

  23. Makinen, N. et al. MED12, the mediator complex subunit 12 gene, is mutated at high frequency in uterine leiomyomas. Science 334, 252–255 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Risheg, H. et al. A recurrent mutation in MED12 leading to R961W causes Opitz–Kaveggia syndrome. Nature Genet. 39, 451–453 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Ding, N. et al. Mediator links epigenetic silencing of neuronal gene expression with X-linked mental retardation. Mol. Cell 31, 347–359 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Turunen, M. et al. Uterine leiomyoma-linked MED12 mutations disrupt mediator-associated CDK activity. Cell Rep. 7, 654–660 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Donner, A. J., Ebmeier, C. C., Taatjes, D. J. & Espinosa, J. M. CDK8 is a positive regulator of transcriptional elongation within the serum response network. Nature Struct. Mol. Biol. 17, 194–201 (2010).

    Article  CAS  Google Scholar 

  28. Galbraith, M. D. et al. HIF1A employs CDK8–Mediator to stimulate RNAPII elongation in response to hypoxia. Cell 153, 1327–1339 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Alarcon, C. et al. Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-β pathways. Cell 139, 757–769 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bancerek, J. et al. CDK8 kinase phosphorylates transcription factor STAT1 to selectively regulate the interferon response. Immunity 38, 250–262 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hirst, M., Kobor, M. S., Kuriakose, N., Greenblatt, J. & Sadowski, I. GAL4 is regulated by the RNA polymerase II holoenzyme-associated cyclin-dependent protein kinase SRB10/CDK8. Mol. Cell 3, 673–678 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Vincent, O. et al. Interaction of the Srb10 kinase with Sip4, a transcriptional activator of gluconeogenic genes in Saccharomyces cerevisiae. Mol. Cell. Biol. 21, 5790–5796 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Morris, E. J. et al. E2F1 represses β-catenin transcription and is antagonized by both pRB and CDK8. Nature 455, 552–556 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhao, X. et al. Regulation of lipogenesis by cyclin-dependent kinase 8-mediated control of SREBP-1. J. Clin. Invest. 122, 2417–2427 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Daniels, D. L. et al. Mutual exclusivity of MED12/MED12L, MED13/13L, and CDK8/19 paralogs revealed within the CDK–Mediator kinase module. J. Proteomics Bioinform http://dx.doi.org/10.4172/jpb.S2-004 (2013).

  36. Muncke, N. et al. Missense mutations and gene interruption in PROSIT240, a novel TRAP240-like gene, in patients with congenital heart defect (transposition of the great arteries). Circulation 108, 2843–2850 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Mukhopadhyay, A. et al. CDK19 is disrupted in a female patient with bilateral congenital retinal folds, microcephaly and mild mental retardation. Hum. Genet. 128, 281–291 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Toth-Petroczy, A. et al. Malleable machines in transcription regulation: the mediator complex. PLoS Comput. Biol. 4, e1000243 (2008). This study reveals that yeast and human Mediator contain a preponderance of predicted IDRs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Asturias, F. J., Jiang, Y. W., Myers, L. C., Gustafsson, C. M. & Kornberg, R. D. Conserved structures of mediator and RNA polymerase II holoenzyme. Science 283, 985–987 (1999). This paper provides the first insights into Mediator structure and the nature of the Mediator–Pol II interaction.

    Article  CAS  PubMed  Google Scholar 

  40. Cai, G., Imasaki, T., Takagi, Y. & Asturias, F. A. Mediator structural conservation and implications for the regulation mechanism. Structure 17, 559–567 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Meyer, K. D., Lin, S., Bernecky, C., Gao, Y. & Taatjes, D. J. p53 activates transcription by directing structural shifts in Mediator. Nature Struct. Mol. Biol. 17, 753–760 (2010). This study gives structural and functional evidence that TF-induced structural shifts in Mediator are required for the activation of transcription.

    Article  CAS  Google Scholar 

  42. Naar, A. M., Taatjes, D. J., Zhai, W., Nogales, E. & Tjian, R. Human CRSP interacts with RNA polymerase II CTD and adopts a specific CTD-bound conformation. Genes Dev. 16, 1339–1344 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ebmeier, C. C. & Taatjes, D. J. Activator-Mediator binding regulates Mediator–cofactor interactions. Proc. Natl Acad. Sci. USA 107, 11283–11288 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Tsai, K. L. et al. Subunit architecture and functional modular rearrangements of the transcriptional mediator complex. Cell 157, 1430–1444 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wang, X. et al. Redefining the modular organization of the core Mediator complex. Cell Res. 24, 796–808 (2014). References 44 and 45 redefine previous models of yeast Mediator subunit architecture; reference 44 also provides the highest-resolution structure of yeast Mediator to date.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Dotson, M. R. et al. Structural organization of yeast and mammalian mediator complexes. Proc. Natl Acad. Sci. USA 97, 14307–14310 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Reeves, W. M. & Hahn, S. Activator-independent functions of the yeast Mediator Sin4 complex in preinitiation complex formation and transcription reinitiation. Mol. Cell. Biol. 23, 349–358 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sakurai, H. & Fukasawa, T. Functional connections between mediator components and general transcription factors of Saccharomyces cerevisiae. J. Biol. Chem. 275, 37251–37256 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Sakurai, H., Kim, Y. J., Ohishi, T., Kornberg, R. D. & Fukasawa, T. The yeast GAL11 protein binds to the transcription factor IIE through GAL11 regions essential for its in vivo function. Proc. Natl Acad. Sci. USA 93, 9488–9492 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ansari, S. A. et al. Distinct role of Mediator tail module in regulation of SAGA-dependent, TATA-containing genes in yeast. EMBO J. 31, 44–57 (2012).

    Article  CAS  PubMed  Google Scholar 

  51. Lim, M. K. et al. Gal11p dosage-compensates transcriptional activator deletions via Taf14p. J. Mol. Biol. 374, 9–23 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Guglielmi, B. et al. A high resolution protein interaction map of the yeast Mediator complex. Nucleic Acids Res. 32, 5379–5391 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Cevher, M. A. et al. Reconstitution of active human core Mediator complex reveals a critical role of the MED14 subunit. Nature Struct. Mol. Biol. 21, 1028–1034 (2014). This study demonstrates that an active, partial Mediator complex can be reconstituted from the recombinant expression of individual subunits and reveals key roles for MED14 and MED26.

    Article  CAS  Google Scholar 

  54. Imasaki, T. et al. Architecture of the Mediator head module. Nature 475, 240–243 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Lariviere, L. et al. Model of the Mediator middle module based on protein cross-linking. Nucleic Acids Res. 41, 9266–9273 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Lariviere, L. et al. Structure of the Mediator head module. Nature 492, 448–451 (2012).

    Article  CAS  PubMed  Google Scholar 

  57. Robinson, P. J., Bushnell, D. A., Trnka, M. J., Burlingame, A. L. & Kornberg, R. D. Structure of the mediator head module bound to the carboxy-terminal domain of RNA polymerase II. Proc. Natl Acad. Sci. USA 109, 17931–17935 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Bernecky, C., Grob, P., Ebmeier, C. C., Nogales, E. & Taatjes, D. J. Molecular architecture of the human Mediator–RNA polymerase II–TFIIF assembly. PLoS Biol. 9, e1000603 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Davis, J. A., Takagi, Y., Kornberg, R. D. & Asturias, F. A. Structure of the yeast RNA polymerase II holoenzyme: Mediator conformation and polymerase interaction. Mol. Cell 10, 409–415 (2002).

    Article  CAS  PubMed  Google Scholar 

  60. Holstege, F. C. et al. Dissecting the regulatory circuitry of a eukaryotic genome. Cell 95, 717–728 (1998). This paper demonstrates a global requirement for Mediator and TFIIH for Pol II transcription in yeast.

    Article  CAS  PubMed  Google Scholar 

  61. Myers, L. C., Gustafsson, C. M., Hayashibara, K. C., Brown, P. O. & Kornberg, R. D. Mediator protein mutations that selectively abolish activated transcription. Proc. Natl Acad. Sci. USA 96, 67–72 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kim, Y., Bjorklund, S., Li, Y., Sayre, M. H. & Kornberg, R. D. A multiprotein mediator of transcriptional activation and its interaction with the C-terminal repeat domain of RNA polymerase II. Cell 77, 599–608 (1994).

    Article  CAS  PubMed  Google Scholar 

  63. Myers, L. C. et al. The Med proteins of yeast and their function through the RNA polymerase II carboxy-terminal domain. Genes Dev. 12, 45–54 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Thompson, C. M., Koleske, A. J., Chao, D. M. & Young, R. A. A multisubunit complex associated with the RNA polymerase II CTD and TATA-binding protein in yeast. Cell 73, 1361–1375 (1993).

    Article  CAS  PubMed  Google Scholar 

  65. Guermah, M., Tao, Y. & Roeder, R. G. Positive and negative TAF(II) functions that suggest a dynamic TFIID structure and elicit synergy with traps in activator-induced transcription. Mol. Cell. Biol. 21, 6882–6894 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Johnson, K. M., Wang, J., Smallwood, A., Arayata, C. & Carey, M. TFIID and human mediator coactivator complexes assemble cooperatively on promoter DNA. Genes Dev. 16, 1852–1863 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Marr, M. T., Isogai, Y., Wright, K. J. & Tjian, R. Coactivator cross-talk specifies transcriptional output. Genes Dev. 20, 1458–1469 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Takahashi, H. et al. Human Mediator subunit MED26 functions as a docking site for transcription elongation factors. Cell 146, 92–104 (2011). This study shows a direct role for MED26 in binding the SEC and affecting transcription elongation in human cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Xu, M. et al. Core promoter-selective function of HMGA1 and Mediator in Initiator-dependent transcription. Genes Dev. 25, 2513–2524 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Baek, H. J., Kang, Y. K. & Roeder, R. G. Human Mediator enhances basal transcription by facilitating recruitment of transcription factor IIB during preinitiation complex assembly. J. Biol. Chem. 281, 15172–15181 (2006).

    Article  CAS  PubMed  Google Scholar 

  71. Johnson, K. M. & Carey, M. Assembly of a mediator/TFIID/TFIIA complex bypasses the need for an activator. Curr. Biol. 13, 772–777 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Jishage, M. et al. Transcriptional regulation by Pol II(G) involving mediator and competitive interactions of Gdown1 and TFIIF with Pol II. Mol. Cell 45, 51–63 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Esnault, C. et al. Mediator-dependent recruitment of TFIIH modules in Preinitiation Complex. Mol. Cell 31, 337–346 (2008).

    Article  CAS  PubMed  Google Scholar 

  74. Seizl, M., Lariviere, L., Pfaffeneder, T., Wenzeck, L. & Cramer, P. Mediator head subcomplex Med11/22 contains a common helix bundle building block with a specific function in transcription initiation complex stabilization. Nucleic Acids Res. 39, 6291–6304 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Hu, X. et al. A Mediator-responsive form of metazoan RNA polymerase II. Proc. Natl Acad. Sci. USA 103, 9506–9511 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Cheng, B. et al. Functional association of Gdown1 with RNA polymerase II poised on human genes. Mol. Cell 45, 38–50 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wu, Y. M. et al. Regulation of mammalian transcription by Gdown1 through a novel steric crosstalk revealed by cryo-EM. EMBO J. 31, 3575–3587 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Svejstrup, J. Q. et al. Evidence for a mediator cycle at the initiation of transcription. Proc. Natl Acad. Sci. USA 94, 6075–6078 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Corden, J. L. RNA polymerase II C-terminal domain: tethering transcription to transcript and template. Chem. Rev. 113, 8423–8455 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Eick, D. & Geyer, M. The RNA polymerase II carboxy-terminal domain (CTD) code. Chem. Rev. 113, 8456–8490 (2013).

    Article  CAS  PubMed  Google Scholar 

  81. Boeing, S., Rigault, C., Heidemann, M., Eick, D. & Meisterernst, M. RNA polymerase II C-terminal heptarepeat domain Ser-7 phosphorylation is established in a mediator-dependent fashion. J. Biol. Chem. 285, 188–196 (2010).

    Article  CAS  PubMed  Google Scholar 

  82. Nair, D., Kim, Y. & Myers, L. C. Mediator and TFIIH govern carboxy-terminal domain-dependent transcription in yeast extracts. J. Biol. Chem. 280, 33739–33748 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Jeronimo, C. & Robert, F. Kin28 regulates the transient association of Mediator with core promoters. Nature Struct. Mol. Biol. 21, 449–455 (2014).

    Article  CAS  Google Scholar 

  84. Wong, K. H., Jin, Y. & Struhl, K. TFIIH phosphorylation of the Pol II CTD stimulates mediator dissociation from the preinitiation complex and promoter escape. Mol. Cell 54, 601–612 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Rhee, H. S. & Pugh, B. F. Genome-wide structure and organization of eukaryotic pre-initiation complexes. Nature 483, 295–301 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Lee, S. K., Chen, X., Huang, L. & Stargell, L. A. The head module of Mediator directs activation of preloaded RNAPII in vivo. Nucleic Acids Res. 41, 10124–10134 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Core, L. J., Waterfall, J. J. & Lis, J. T. Nascent RNA sequencing reveals widespread pausing and divergent initiation at human promoters. Science 322, 1845–1848 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Seila, A. C. et al. Divergent transcription from active promoters. Science 322, 1849–1851 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Guenther, M. G., Levine, S. S., Boyer, L. A., Jaenisch, R. & Young, R. A. A chromatin landmark and transcription initiation at most promoters in human cells. Cell 130, 77–88 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Muse, G. W. et al. RNA polymerase is poised for activation across the genome. Nature Genet. 39, 1507–1511 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Zeitlinger, J. et al. RNA polymerase stalling at developmental control genes in the Drosophila melanogaster embryo. Nature Genet. 39, 1512–1516 (2007).

    Article  CAS  PubMed  Google Scholar 

  92. Kremer, S. B. et al. Role of Mediator in regulating Pol II elongation and nucleosome displacement in Saccharomyces cerevisiae. Genetics 191, 95–106 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Malik, S., Wallberg, A. E., Kang, Y. K. & Roeder, R. G. TRAP/SMCC/mediator-dependent transcriptional activation from DNA and chromatin templates by orphan nuclear receptor hepatocyte nuclear factor 4. Mol. Cell. Biol. 22, 5626–5637 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Wang, G. et al. Mediator requirement for both recruitment and postrecruitment steps in transcription initiation. Mol. Cell 17, 683–694 (2005).

    Article  CAS  PubMed  Google Scholar 

  95. Adelman, K. & Lis, J. T. Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans. Nature Rev. Genet. 13, 720–731 (2012).

    Article  CAS  PubMed  Google Scholar 

  96. Lin, C. et al. AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. Mol. Cell 37, 429–437 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Luo, Z., Lin, C. & Shilatifard, A. The super elongation complex (SEC) family in transcriptional control. Nature Rev. Mol. Cell Biol. 13, 543–547 (2012).

    Article  CAS  Google Scholar 

  98. Paoletti, A. C. et al. Quantitative proteomic analysis of distinct mammalian Mediator complexes using normalized spectral abundance factors. Proc. Natl Acad. Sci. USA 103, 18928–18933 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Balamotis, M. A. et al. Complexity in transcription control at the activation domain–Mediator interface. Sci. Signal. 2, ra20 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Park, J. M., Werner, J., Kim, J. M., Lis, J. T. & Kim, Y. J. Mediator, not holoenzyme, is directly recruited to the heat shock promoter by HSF upon heat shock. Mol. Cell 8, 9–19 (2001). This is one of the first studies to suggest a role for Mediator in regulating paused or 'post-initiated' Pol II.

    Article  CAS  PubMed  Google Scholar 

  101. Schaaf, C. A. et al. Genome-wide control of RNA polymerase II activity by cohesin. PLoS Genet. 9, e1003382 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Kagey, M. et al. Mediator and cohesin connect gene expression and chromatin architecture. Nature 467, 430–435 (2010). This study uncovers a role for Mediator in regulating genome architecture, implicating Mediator and cohesin in the formation and/or maintenance of enhancer–promoter gene loops in mammalian cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Lin, C., Garruss, A. S., Luo, Z., Guo, F. & Shilatifard, A. The RNA Pol II elongation factor Ell3 marks enhancers in ES cells and primes future gene activation. Cell 152, 144–156 (2013).

    Article  CAS  PubMed  Google Scholar 

  104. Guglielmi, B., Soutourina, J., Esnault, C. & Werner, M. TFIIS elongation factor and Mediator act in conjunction during transcription initiation in vivo. Proc. Natl Acad. Sci. USA 104, 16062–16067 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Kim, B. et al. The transcription elongation factor TFIIS is a component of RNA polymerase II preinitiation complexes. Proc. Natl Acad. Sci. USA 104, 16068–16073 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Nock, A., Ascano, J. M., Barrero, M. J. & Malik, S. Mediator-regulated transcription through the +1 nucleosome. Mol. Cell 48, 837–848 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Malik, S., Barrero, M. J. & Jones, T. Identification of a regulator of transcription elongation as an accessory factor for the human Mediator coactivator. Proc. Natl Acad. Sci. USA 104, 6182–6187 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Larson, D. R. et al. Direct observation of frequency modulated transcription in single cells using light activation. ELife 2, e00750 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Sandaltzopoulos, R. & Becker, P. B. Heat shock factor increases the reinitiation rate from potentiated chromatin templates. Mol. Cell. Biol. 18, 361–367 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Yudkovsky, N., Ranish, J. A. & Hahn, S. A transcription reinitiation intermediate that is stabilized by activator. Nature 408, 225–229 (2000). This study provides evidence for a re-initiation 'scaffold' form of PIC that contains most PIC factors, including Mediator.

    Article  CAS  PubMed  Google Scholar 

  111. Reid, G. et al. Cyclic, proteasome-mediated turnover of unliganded and liganded ERα on responsive promoters is an integral feature of estrogen signaling. Mol. Cell 11, 695–707 (2003).

    Article  CAS  PubMed  Google Scholar 

  112. Andrau, J. et al. Genome-wide location of the coactivator Mediator: binding without activation and transient Cdk8 interaction on DNA. Mol. Cell 22, 179–192 (2006). This is one of the first studies to reveal colocalization of Cdk8 with Mediator across the yeast genome.

    Article  CAS  PubMed  Google Scholar 

  113. Mo, X., Kowenz-Leutz, E., Xu, H. & Leutz, A. Ras induces mediator complex exchange on C/EBPb. Mol. Cell 13, 241–250 (2004).

    Article  CAS  PubMed  Google Scholar 

  114. Kim, Y. K. et al. Recruitment of TFIIH to the HIV LTR is a rate-limiting step in the emergence of HIV from latency. EMBO J. 25, 3596–3604 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Pavri, R. et al. PARP-1 determines specificity in a retinoid signaling pathway via direct modulation of mediator. Mol. Cell 18, 83–96 (2005). This is the first study to reveal a potential means by which CDK8 module–Mediator interactions are regulated in mammalian cells.

    Article  CAS  PubMed  Google Scholar 

  116. Ansari, S. A. et al. Mediator, TATA-binding protein, and RNA polymerase II contribute to low histone occupancy at active gene promoters in yeast. J. Biol. Chem. 289, 14981–14995 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Gilchrist, D. A. et al. Pausing of RNA polymerase II disrupts DNA-specified nucleosome organization to enable precise gene regulation. Cell 143, 540–551 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Sharma, V. M., Li, B. & Reese, J. C. SWI/SNF-dependent chromatin remodeling of RNR3 requires TAF(II)s and the general transcription machinery. Genes Dev. 17, 502–515 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Lin, J. J. et al. Mediator coordinates PIC assembly with recruitment of CHD1. Genes Dev. 25, 2198–2209 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Lemieux, K. & Gaudreau, L. Targeting of Swi/Snf to the yeast GAL1 UAS G requires the Mediator, TAF IIs, and RNA polymerase II. EMBO J. 23, 4040–4050 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Vilar, J. M. & Saiz, L. DNA looping in gene regulation: from the assembly of macromolecular complexes to the control of transcriptional noise. Curr. Opin. Genet. Dev. 15, 136–144 (2005).

    Article  CAS  PubMed  Google Scholar 

  122. Levine, M., Cattoglio, C. & Tjian, R. Looping back to leap forward: transcription enters a new era. Cell 157, 13–25 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Fanucchi, S., Shibayama, Y., Burd, S., Weinberg, M. S. & Mhlanga, M. M. Chromosomal contact permits transcription between coregulated genes. Cell 155, 606–620 (2013).

    Article  CAS  PubMed  Google Scholar 

  124. Li, G. et al. Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell 148, 84–98 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Deng, W. et al. Controlling long-range genomic interactions at a native locus by targeted tethering of a looping factor. Cell 149, 1233–1244 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Kieffer-Kwon, K. R. et al. Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation. Cell 155, 1507–1520 (2013).

    Article  CAS  PubMed  Google Scholar 

  127. Sanyal, A., Lajoie, B. R., Jain, G. & Dekker, J. The long-range interaction landscape of gene promoters. Nature 489, 109–113 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Phillips-Cremins, J. E. et al. Architectural protein subclasses shape 3D organization of genomes during lineage commitment. Cell 153, 1281–1295 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013).

    Article  CAS  PubMed  Google Scholar 

  130. Muto, A. et al. Nipbl and Mediator cooperatively regulate gene expression to control limb development. PLoS Genet. 10, e1004671 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Dobi, K. C. & Winston, F. Analysis of transcriptional activation at a distance in Saccharomyces cerevisiae. Mol. Cell. Biol. 27, 5575–5586 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Mukundan, B. & Ansari, A. Srb5/Med18-mediated termination of transcription is dependent on gene looping. J. Biol. Chem. 288, 11384–11394 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Orom, U. A. et al. Long noncoding RNAs with enhancer-like function in human cells. Cell 143, 46–58 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Lai, F. et al. Activating RNAs associate with Mediator to enhance chromatin architecture and transcription. Nature 494, 497–501 (2013). This study demonstrates that ncRNAs transcribed from distal sequence elements can interact with Mediator to regulate gene looping to the promoter and transcription activation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Wang, D. et al. Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature 474, 390–394 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Hah, N., Murakami, S., Nagari, A., Danko, C. G. & Kraus, W. L. Enhancer transcripts mark active estrogen receptor binding sites. Genome Res. 23, 1210–1223 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Lam, M. T. et al. Rev–Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription. Nature 498, 511–515 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Li, W. et al. Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature 498, 516–520 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Hsieh, C. L. et al. Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation. Proc. Natl Acad. Sci. USA 111, 7319–7324 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Step, S. E. et al. Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancers. Genes Dev. 28, 1018–1028 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Bartolomei, M. S., Halden, N. F., Cullen, C. R. & Corden, J. L. Genetic analysis of the repetitive carboxyl-terminal domain of the largest subunit of mouse RNA polymerase II. Mol. Cell. Biol. 8, 330–339 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Gerber, H. P. et al. RNA polymerase II C-terminal domain required for enhancer-driven transcription. Nature 374, 660–662 (1995).

    Article  CAS  PubMed  Google Scholar 

  143. Oya, E. et al. Mediator directs co-transcriptional heterochromatin assembly by RNA interference-dependent and -independent pathways. PLoS Genet. 9, e1003677 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Carlsten, J. O. et al. Mediator promotes CENP-a incorporation at fission yeast centromeres. Mol. Cell. Biol. 32, 4035–4043 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Thorsen, M., Hansen, H., Venturi, M., Holmberg, S. & Thon, G. Mediator regulates non-coding RNA transcription at fission yeast centromeres. Epigenetics Chromatin 5, 19 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Lenstra, T. L. et al. The specificity and topology of chromatin interaction pathways in yeast. Mol. Cell 42, 536–549 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Peng, J. & Zhou, J. Q. The tail-module of yeast Mediator complex is required for telomere heterochromatin maintenance. Nucleic Acids Res. 40, 581–593 (2012).

    Article  CAS  PubMed  Google Scholar 

  148. Suzuki, Y. & Nishizawa, M. The yeast GAL11 protein is involved in regulation of the structure and the position effect of telomeres. Mol. Cell. Biol. 14, 3791–3799 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Zhu, X. et al. Mediator influences telomeric silencing and cellular life span. Mol. Cell. Biol. 31, 2413–2421 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Marr, S. K., Lis, J. T., Treisman, J. E. & Marr, M. T. The metazoan-specific Mediator subunit 26 (Med26) is essential for viability and is found at both active genes and pericentric heterochromatin in Drosophila. Mol. Cell. Biol. 34, 2710–2720 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Smallwood, A., Black, J. C., Tanese, N., Pradhan, S. & Carey, M. HP1-mediated silencing targets Pol II coactivator complexes. Nature Struct. Mol. Biol. 15, 318–320 (2008).

    Article  CAS  Google Scholar 

  152. Jiang, Y. W. et al. Mammalian mediator of transcriptional regulation and its possible role as an end-point of signal transduction pathways. Proc. Natl Acad. Sci. USA 95, 8538–8543 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Gaarenstroom, T. & Hill, C. S. TGF-β signaling to chromatin: how SMADs regulate transcription during self-renewal and differentiation. Semin. Cell Dev. Biol. 32, 107–118 (2014).

    Article  CAS  PubMed  Google Scholar 

  154. Kato, Y., Habas, R., Katsuyama, Y., Naar, A. & He, X. A component of the ARC/Mediator complex required for TGF β/Nodal signalling. Nature 418, 641–646 (2002).

    Article  CAS  PubMed  Google Scholar 

  155. Zhao, M. et al. Mediator MED15 modulates transforming growth factor β (TGFβ)/Smad signaling and breast cancer cell metastasis. J. Mol. Cell. Biol. 5, 57–60 (2013).

    Article  PubMed  Google Scholar 

  156. Huang, S. et al. MED12 controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling. Cell 151, 937–950 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Knuesel, M. T., Meyer, K. D., Donner, A. J., Espinosa, J. M. & Taatjes, D. J. The human CDK8 subcomplex is a histone kinase that requires Med12 for activity and can function independently of Mediator. Mol. Cell. Biol. 29, 650–661 (2009).

    Article  CAS  PubMed  Google Scholar 

  158. Gao, S. et al. Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGF-β signaling. Mol. Cell 36, 457–468 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Kahn, M. Can we safely target the WNT pathway? Nature Rev. Drug Discov. 13, 513–532 (2014).

    Article  CAS  Google Scholar 

  160. Carrera, I., Janody, F., Leeds, N., Duveau, F. & Treisman, J. E. Pygopus activates Wingless target gene transcription through the mediator complex subunits Med12 and Med13. Proc. Natl Acad. Sci. USA 105, 6644–6649 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Rocha, P. P., Scholze, M., Bleiss, W. & Schrewe, H. Med12 is essential for early mouse development and for canonical Wnt and Wnt/PCP signaling. Development 137, 2723–2731 (2010).

    Article  CAS  PubMed  Google Scholar 

  162. Kim, S., Xu, X., Hecht, A. & Boyer, T. G. Mediator is a transducer of Wnt/β-catenin signaling. J. Biol. Chem. 281, 14066–14075 (2006).

    Article  CAS  PubMed  Google Scholar 

  163. Zhang, H. & Emmons, S. W. A C. elegans mediator protein confers regulatory selectivity on lineage-specific expression of a transcription factor gene. Genes Dev. 14, 2161–2172 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Zhao, J., Ramos, R. & Demma, M. CDK8 regulates E2F1 transcriptional activity through S375 phosphorylation. Oncogene 32, 3520–3530 (2012).

    Article  CAS  PubMed  Google Scholar 

  165. Firestein, R. et al. CDK8 is a colorectal cancer oncogene that regulates β-catenin activity. Nature 455, 547–551 (2008). References 33 and 165 identify CDK8 as a colon cancer oncogene.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Kasza, A. Signal-dependent Elk-1 target genes involved in transcript processing and cell migration. Biochim. Biophys. Acta 1829, 1026–1033 (2013).

    Article  CAS  PubMed  Google Scholar 

  167. Wang, W. et al. Mediator MED23 links insulin signaling to the adipogenesis transcription cascade. Dev. Cell 16, 764–771 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Yin, J. W. et al. Mediator MED23 plays opposing roles in directing smooth muscle cell and adipocyte differentiation. Genes Dev. 26, 2192–2205 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Belakavadi, M., Pandey, P. K., Vijayvargia, R. & Fondell, J. D. MED1 phosphorylation promotes its association with Mediator: implications for nuclear receptor signaling. Mol. Cell. Biol. 28, 3932–3942 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Pandey, P. K. et al. Activation of TRAP/Mediator subunit TRAP220/Med1 is regulated by mitogen-activated protein kinase-dependent phosphorylation. Mol. Cell. Biol. 25, 10695–10710 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Papantonis, A. & Cook, P. R. Transcription factories: genome organization and gene regulation. Chem. Rev. 113, 8683–8705 (2013).

    Article  CAS  PubMed  Google Scholar 

  172. Han, T. W. et al. Cell-free formation of RNA granules: bound RNAs identify features and components of cellular assemblies. Cell 149, 768–779 (2012).

    Article  CAS  PubMed  Google Scholar 

  173. Kato, M. et al. Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels. Cell 149, 753–767 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Tompa, P. Hydrogel formation by multivalent IDPs: a reincarnation of the microtrabecular lattice? Intrinsically Disordered Proteins 1, e24068 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  175. Takagi, Y. & Kornberg, R. D. Mediator as a general transcription factor. J. Biol. Chem. 281, 80–89 (2006).

    Article  CAS  PubMed  Google Scholar 

  176. Bourbon, H. M. Comparative genomics supports a deep evolutionary origin for the large, four-module transcriptional mediator complex. Nucleic Acids Res. 36, 3993–4008 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. van der Lee, R. et al. Classification of intrinsically disordered regions and proteins. Chem. Rev. 114, 6589–6631 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Madhani, H. D. The frustrated gene: origins of eukaryotic gene expression. Cell 155, 744–749 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Kuuluvainen, E. et al. Cyclin-dependent kinase 8 module expression profiling reveals requirement of Mediator subunits 12 and 13 for transcription of Serpent-dependent innate immunity genes in Drosophila. J. Biol. Chem. 289, 16252–16261 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Napoli, C., Sessa, M., Infante, T. & Casamassimi, A. Unraveling framework of the ancestral Mediator complex in human diseases. Biochimie 94, 579–587 (2012).

    Article  CAS  PubMed  Google Scholar 

  181. Phillips, A. J. & Taatjes, D. J. Small molecule probes to target the human Mediator complex. Isr. J. Chem. 53, 588–595 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Milbradt, A. G. et al. Structure of the VP16 transactivator target in the Mediator. Nature Struct. Mol. Biol. 18, 410–415 (2011).

    Article  CAS  Google Scholar 

  183. Vojnic, E. et al. Structure and VP16 binding of the Mediator Med25 activator interaction domain. Nature Struct. Mol. Biol. 18, 404–409 (2011).

    Article  CAS  Google Scholar 

  184. Yang, F. et al. An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis. Nature 442, 700–704 (2006).

    Article  CAS  PubMed  Google Scholar 

  185. Loven, J. et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153, 320–334 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Whyte, W. A. et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153, 307–319 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Gerstein, M. B. et al. Integrative analysis of the Caenorhabditis elegans genome by the modENCODE project. Science 330, 1775–1787 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. modENCODE Consortium et al. Identification of functional elements and regulatory circuits by Drosophila modENCODE. Science 330, 1787–1797 (2010).

  189. Li, Q., Peterson, K. R., Fang, X. & Stamatoyannopoulos, G. Locus control regions. Blood 100, 3077–3086 (2002).

    Article  CAS  PubMed  Google Scholar 

  190. Darnell, J. E. Jr. Reflections on the history of pre-mRNA processing and highlights of current knowledge: a unified picture. RNA 19, 443–460 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Grunberg, S. & Hahn, S. Structural insights into transcription initiation by RNA polymerase II. Trends Biochem. Sci. 38, 603–611 (2013).

    Article  CAS  PubMed  Google Scholar 

  192. Thomas, M. C. & Chiang, C. M. The general transcription machinery and general cofactors. Crit. Rev. Biochem. Mol. Biol. 41, 105–178 (2006).

    Article  CAS  PubMed  Google Scholar 

  193. He, Y., Fang, J., Taatjes, D. J. & Nogales, E. Structural visualization of key steps in human transcription initiation. Nature 495, 481–486 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Murakami, K. et al. Architecture of an RNA polymerase II transcription pre-initiation complex. Science 342, 1238724 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Muhlbacher, W. et al. Conserved architecture of the core RNA polymerase II initiation complex. Nature Commun. 5, 4310 (2014).

    Article  CAS  Google Scholar 

  196. Bieniossek, C. et al. The architecture of human general transcription factor TFIID core complex. Nature 493, 699–702 (2013).

    Article  CAS  PubMed  Google Scholar 

  197. Bernecky, C. & Taatjes, D. J. Activator–Mediator binding stabilizes RNA polymerase II orientation within the human Mediator–RNA polymerase II–TFIIF assembly. J. Mol. Biol. 417, 387–394 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Elmlund, H. et al. The cyclin-dependent kinase 8 module sterically blocks Mediator interactions with RNA polymerase II. Proc. Natl Acad. Sci. USA 103, 15788–15793 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank A. Shilatifard and the reviewers for comments on the manuscript. They apologize that they could not discuss other important and relevant research owing to space and citation limits. D.J.T.'s laboratory is supported by the US National Science Foundation (MCB-1244175) and the US National Cancer Institute (CA175849; CA1707041; CA175448). B.L.A. has been supported in part by the US National Institutes of Health (T32 GM08759).

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Sequence conservation between yeast and human Mediator (PDF 546 kb)

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Glossary

Mediator complex

(Also known as core Mediator). The 21-subunit (Saccharomyces cerevisiae) or 26-subunit (human) complex that does not contain the cyclin-dependent kinase 8 module.

Enhancer–promoter gene looping

Looping of genomic DNA that juxtaposes an enhancer, which may be dozens (or more) of kilobases away, and a promoter.

Cyclin-dependent kinase 8 module

(CDK8 module). A group of four subunits, CDK8, CCNC, MED12 and MED13, that can reversibly associate with Mediator.

CDK8–Mediator

Mediator bound to the four-subunit cyclin-dependent kinase 8 (CDK8) module; in metazoans, this complex lacks the MED26 subunit.

Intrinsically disordered regions

(IDRs). Protein sequences that do not adopt a fixed 3D structure, yet may do so upon binding to another protein.

Uterine leiomyomas

Benign tumours of smooth muscle cells originating from the uterus.

Head module

The yeast Mediator subunits Med6, Med8, Med11, Med17, Med18, Med19, Med20 and Med22.

Middle module

The yeast Mediator subunits Med1, Med4, Med7, Med9, Med10, Med21 and Med31.

Tail module

The yeast Mediator subunits Med2, Med3, Med5, Med14, Med15 and Med16.

Crystal structure docking

Fitting an existing crystal structure into a larger structural model.

Open complex

An RNA polymerase II complex in which double-stranded DNA is unwound to single-stranded DNA around the transcription start site; an open complex is required to initiate transcription.

CTD repeats

A series of YSPTSPS repeats within the carboxy-terminal domain (CTD) of the largest subunit of RNA polymerase II.

Chromatin immunoprecipitation followed by sequencing

(ChIP–seq). Immunoprecipitation of a protein followed by DNA sequencing to determine the binding sites of the protein throughout the genome.

Sequential chromatin immunoprecipitation

(ChIP–reChIP). Two sequential ChIP experiments designed to determine the co-occupancy of two different proteins at or around the same DNA sequence.

Operons

Groups of genes that are sequentially arranged in the genome and that are under the control of a single promoter.

Pericentromeric heterochromatin

Heterochromatin regions near chromosomal centromeres; the primary sites of sister chromatid cohesion.

Telomeric heterochromatin

Heterochromatin regions near telomeres, which are repetitive regions of DNA at the ends of chromosomes.

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Allen, B., Taatjes, D. The Mediator complex: a central integrator of transcription. Nat Rev Mol Cell Biol 16, 155–166 (2015). https://doi.org/10.1038/nrm3951

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