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Mechanisms of Mediator complex action in transcriptional activation

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Abstract

Mediator is a large multisubunit complex that plays a central role in the regulation of RNA Pol II transcribed genes. Conserved in overall structure and function among eukaryotes, Mediator comprises 25–30 protein subunits that reside in four distinct modules, termed head, middle, tail, and CDK8/kinase. Different subunits of Mediator contact other transcriptional regulators including activators, co-activators, general transcription factors, subunits of RNA Pol II, and specifically modified histones, leading to the regulated expression of target genes. This review is focused on the interactions of specific Mediator subunits with diverse transcription regulators and how those interactions contribute to Mediator function in transcriptional activation.

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Abbreviations

ER:

Estrogen receptor

GTF:

General transcription factor

HNF4:

Hepatic nuclear factor 4

JA:

Jasmonic acid

NR:

Nuclear receptor

PIC:

Pre-initiation complex

Pol II:

RNA polymerase II

References

  1. Lemon B, Tjian R (2000) Orchestrated response: a symphony of transcription factors for gene control. Genes Dev 14:2551–2569

    Article  PubMed  CAS  Google Scholar 

  2. Butler JE, Kadonaga JT (2002) The RNA polymerase II core promoter: a key component in the regulation of gene expression. Genes Dev 16:2583–2592

    Article  PubMed  CAS  Google Scholar 

  3. Thomas MC, Chiang CM (2006) The general transcription machinery and general cofactors. Crit Rev Biochem Mol Biol 41:105–178

    Article  PubMed  CAS  Google Scholar 

  4. Belotserkovskaya R, Berger SL (1999) Interplay between chromatin modifying and remodeling complexes in transcriptional regulation. Crit Rev Eukaryot Gene Expr 9:221–230

    Article  PubMed  CAS  Google Scholar 

  5. Cosma MP, Tanaka T, Nasmyth K (1999) Ordered recruitment of transcription and chromatin remodeling factors to a cell cycle—and developmentally regulated promoter. Cell 97:299–311

    Article  PubMed  CAS  Google Scholar 

  6. Helmlinger D, Marguerat S, Villen J, Swaney DL, Gygi SP, Bahler J, Winston F (2011) Tra1 has specific regulatory roles, rather than global functions, within the SAGA co-activator complex. EMBO J 30:2843–2852

    Article  PubMed  CAS  Google Scholar 

  7. Timmers HT, Tora L (2005) SAGA unveiled. Trends Biochem Sci 30:7–10

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  9. Myers LC, Kornberg RD (2000) Mediator of transcriptional regulation. Annu Rev Biochem 69:729–749

    Article  PubMed  CAS  Google Scholar 

  10. Guglielmi B, van Berkum NL, Klapholz B, Bijma T, Boube M, Boschiero C, Bourbon HM, Holstege FC, Werner M (2004) A high resolution protein interaction map of the yeast mediator complex. Nucleic Acids Res 32:5379–5391

    Article  PubMed  CAS  Google Scholar 

  11. Lariviere L, Plaschka C, Seizl M, Wenzeck L, Kurth F, Cramer P (2012) Structure of the mediator head module. Nature 492:448–451

    Article  PubMed  CAS  Google Scholar 

  12. Asturias FJ, Jiang YW, Myers LC, Gustafsson CM, Kornberg RD (1999) Conserved structures of mediator and RNA polymerase II holoenzyme. Science 283:985–987

    Article  PubMed  CAS  Google Scholar 

  13. Dotson MR, Yuan CX, Roeder RG, Myers LC, Gustafsson CM, Jiang YW, Li Y, Kornberg RD, Asturias FJ (2000) Structural organization of yeast and mammalian mediator complexes. Proc Natl Acad Sci USA 97:14307–14310

    Article  PubMed  CAS  Google Scholar 

  14. Brzovic PS, Heikaus CC, Kisselev L, Vernon R, Herbig E, Pacheco D, Warfield L, Littlefield P, Baker D, Klevit RE, Hahn S (2011) The acidic transcription activator Gcn4 binds the mediator subunit Gal11/Med15 using a simple protein interface forming a fuzzy complex. Mol Cell 44:942–953

    Article  PubMed  CAS  Google Scholar 

  15. Vojnic E, Mourao A, Seizl M, Simon B, Wenzeck L, Lariviere L, Baumli S, Baumgart K, Meisterernst M, Sattler M, Cramer P (2011) Structure and VP16 binding of the mediator Med25 activator interaction domain. Nat Struct Mol Biol 18:404–409

    Article  PubMed  CAS  Google Scholar 

  16. Lewis BA, Reinberg D (2003) The mediator coactivator complex: functional and physical roles in transcriptional regulation. J Cell Sci 116:3667–3675

    Article  PubMed  CAS  Google Scholar 

  17. Malik S, Roeder RG (2010) The metazoan mediator co-activator complex as an integrative hub for transcriptional regulation. Nat Rev Genet 11:761–772

    Article  PubMed  CAS  Google Scholar 

  18. Borggrefe T, Yue X (2011) Interactions between subunits of the mediator complex with gene-specific transcription factors. Semin Cell Dev Biol 22:759–768

    Article  PubMed  CAS  Google Scholar 

  19. Takagi Y, Calero G, Komori H, Brown JA, Ehrensberger AH, Hudmon A, Asturias F, Kornberg RD (2006) Head module control of mediator interactions. Mol Cell 23:355–364

    Article  PubMed  CAS  Google Scholar 

  20. Esnault C, Ghavi-Helm Y, Brun S, Soutourina J, Van Berkum N, Boschiero C, Holstege F, Werner M (2008) Mediator-dependent recruitment of TFIIH modules in preinitiation complex. Mol Cell 31:337–346

    Article  PubMed  CAS  Google Scholar 

  21. Cai G, Imasaki T, Yamada K, Cardelli F, Takagi Y, Asturias FJ (2010) Mediator head module structure and functional interactions. Nat Struct Mol Biol 17:273–279

    Article  PubMed  CAS  Google Scholar 

  22. Bernecky C, Grob P, Ebmeier CC, Nogales E, Taatjes DJ (2011) Molecular architecture of the human mediator-RNA polymerase II-TFIIF assembly. PLoS Biol 9:e1000603

    Article  PubMed  CAS  Google Scholar 

  23. Soutourina J, Wydau S, Ambroise Y, Boschiero C, Werner M (2011) Direct interaction of RNA polymerase II and mediator required for transcription in vivo. Science 331:1451–1454

    Article  PubMed  CAS  Google Scholar 

  24. Bjorklund S, Gustafsson CM (2005) The yeast mediator complex and its regulation. Trends Biochem Sci 30:240–244

    Article  PubMed  CAS  Google Scholar 

  25. Kremer SB, Kim S, Jeon JO, Moustafa YW, Chen A, Zhao J, Gross DS (2012) Role of mediator in regulating Pol II elongation and nucleosome displacement in Saccharomyces cerevisiae. Genetics 191:95–106

    Article  PubMed  CAS  Google Scholar 

  26. Takahashi H, Parmely TJ, Sato S, Tomomori-Sato C, Banks CA, Kong SE, Szutorisz H, Swanson SK, Martin-Brown S, Washburn MP, Florens L, Seidel CW, Lin C, Smith ER, Shilatifard A, Conaway RC, Conaway JW (2011) Human mediator subunit MED26 functions as a docking site for transcription elongation factors. Cell 146:92–104

    Article  PubMed  CAS  Google Scholar 

  27. Donner AJ, Ebmeier CC, Taatjes DJ, Espinosa JM (2010) CDK8 is a positive regulator of transcriptional elongation within the serum response network. Nat Struct Mol Biol 17:194–201

    Article  PubMed  CAS  Google Scholar 

  28. Mukundan B, Ansari A (2011) Novel role for mediator complex subunit Srb5/Med18 in termination of transcription. J Biol Chem 286:37053–37057

    Article  PubMed  CAS  Google Scholar 

  29. Huang Y, Li W, Yao X, Lin QJ, Yin JW, Liang Y, Heiner M, Tian B, Hui J, Wang G (2012) Mediator complex regulates alternative mRNA processing via the MED23 subunit. Mol Cell 45:459–469

    Article  PubMed  CAS  Google Scholar 

  30. Khorosjutina O, Wanrooij PH, Walfridsson J, Szilagyi Z, Zhu X, Baraznenok V, Ekwall K, Gustafsson CM (2010) A chromatin-remodeling protein is a component of fission yeast mediator. J Biol Chem 285:29729–29737

    Article  PubMed  CAS  Google Scholar 

  31. Kagey MH, Newman JJ, Bilodeau S, Zhan Y, Orlando DA, van Berkum NL, Ebmeier CC, Goossens J, Rahl PB, Levine SS, Taatjes DJ, Dekker J, Young RA (2010) Mediator and cohesin connect gene expression and chromatin architecture. Nature 467:430–435

    Article  PubMed  CAS  Google Scholar 

  32. Liu Z, Myers LC (2012) Med5(Nut1) and Med17(Srb4) are direct targets of mediator histone H4 tail interactions. PLoS One 7:e38416

    Article  PubMed  CAS  Google Scholar 

  33. Zhu X, Zhang Y, Bjornsdottir G, Liu Z, Quan A, Costanzo M, Davila Lopez M, Westholm JO, Ronne H, Boone C, Gustafsson CM, Myers LC (2011) Histone modifications influence mediator interactions with chromatin. Nucleic Acids Res 39:8342–8354

    Article  PubMed  CAS  Google Scholar 

  34. Flanagan PM, RD Kelleher, Sayre MH, Tschochner H, Kornberg RD (1991) A mediator required for activation of RNA polymerase II transcription in vitro. Nature 350:436–438

    Article  PubMed  CAS  Google Scholar 

  35. Kornberg RD (2005) Mediator and the mechanism of transcriptional activation. Trends Biochem Sci 30:235–239

    Article  PubMed  CAS  Google Scholar 

  36. Kuras L, Borggrefe T, Kornberg RD (2003) Association of the mediator complex with enhancers of active genes. Proc Natl Acad Sci USA 100:13887–13891

    Article  PubMed  CAS  Google Scholar 

  37. Leroy C, Cormier L, Kuras L (2006) Independent recruitment of mediator and SAGA by the activator Met4. Mol Cell Biol 26:3149–3163

    Article  PubMed  CAS  Google Scholar 

  38. Lin L, Chamberlain L, Zhu LJ, Green MR (2012) Analysis of Gal4-directed transcription activation using Tra1 mutants selectively defective for interaction with Gal4. Proc Natl Acad Sci USA 109:1997–2002

    Article  PubMed  CAS  Google Scholar 

  39. Ang K, Ee G, Ang E, Koh E, Siew WL, Chan YM, Nur S, Tan YS, Lehming N (2012) Mediator acts upstream of the transcriptional activator Gal4. PLoS Biol 10:e1001290

    Article  PubMed  CAS  Google Scholar 

  40. Lee YC, Park JM, Min S, Han SJ, Kim YJ (1999) An activator binding module of yeast RNA polymerase II holoenzyme. Mol Cell Biol 19:2967–2976

    PubMed  CAS  Google Scholar 

  41. Myers LC, Gustafsson CM, Hayashibara KC, Brown PO, Kornberg RD (1999) Mediator protein mutations that selectively abolish activated transcription [see comments]. Proc Natl Acad Sci USA 96:67–72

    Article  PubMed  CAS  Google Scholar 

  42. Zhang F, Sumibcay L, Hinnebusch AG, Swanson MJ (2004) A triad of subunits from the Gal11/tail domain of Srb mediator is an in vivo target of transcriptional activator Gcn4p. Mol Cell Biol 24:6871–6886

    Article  PubMed  CAS  Google Scholar 

  43. Ansari SA, Ganapathi M, Benschop JJ, Holstege FC, Wade JT, Morse RH (2012) Distinct role of mediator tail module in regulation of SAGA-dependent, TATA-containing genes in yeast. EMBO J 31:44–57

    Article  PubMed  CAS  Google Scholar 

  44. van de Peppel J, Kettelarij N, van Bakel H, Kockelkorn TT, van Leenen D, Holstege FC (2005) Mediator expression profiling epistasis reveals a signal transduction pathway with antagonistic submodules and highly specific downstream targets. Mol Cell 19:511–522

    Article  PubMed  CAS  Google Scholar 

  45. Yang F, Vought BW, Satterlee JS, Walker AK, Jim Sun ZY, Watts JL, DeBeaumont R, Saito RM, Hyberts SG, Yang S, Macol C, Iyer L, Tjian R, van den Heuvel S, Hart AC, Wagner G, Naar AM (2006) An ARC/mediator subunit required for SREBP control of cholesterol and lipid homeostasis. Nature 442:700–704

    Article  PubMed  CAS  Google Scholar 

  46. Kato Y, Habas R, Katsuyama Y, Naar AM, He X (2002) A component of the ARC/mediator complex required for TGF beta/Nodal signalling. Nature 418:641–646

    Article  PubMed  CAS  Google Scholar 

  47. Taubert S, Van Gilst MR, Hansen M, Yamamoto KR (2006) A mediator subunit, MDT-15, integrates regulation of fatty acid metabolism by NHR-49-dependent and -independent pathways in C. elegans. Genes Dev 20:1137–1149

    Article  PubMed  CAS  Google Scholar 

  48. Ries D, Meisterernst M (2011) Control of gene transcription by mediator in chromatin. Semin Cell Dev Biol 22:735–740

    Article  PubMed  CAS  Google Scholar 

  49. Thakur JK, Arthanari H, Yang F, Pan SJ, Fan X, Breger J, Frueh DP, Gulshan K, Li DK, Mylonakis E, Struhl K, Moye-Rowley WS, Cormack BP, Wagner G, Naar AM (2008) A nuclear receptor-like pathway regulating multidrug resistance in fungi. Nature 452:604–609

    Article  PubMed  CAS  Google Scholar 

  50. Thakur JK, Arthanari H, Yang F, Chau KH, Wagner G, Naar AM (2009) Mediator subunit Gal11p/MED15 is required for fatty acid-dependent gene activation by yeast transcription factor Oaf1p. J Biol Chem 284:4422–4428

    Article  PubMed  CAS  Google Scholar 

  51. Herbig E, Warfield L, Fish L, Fishburn J, Knutson BA, Moorefield B, Pacheco D, Hahn S (2010) Mechanism of mediator recruitment by tandem Gcn4 activation domains and three Gal11 activator-binding domains. Mol Cell Biol 30:2376–2390

    Article  PubMed  CAS  Google Scholar 

  52. Jedidi I, Zhang F, Qiu H, Stahl SJ, Palmer I, Kaufman JD, Nadaud PS, Mukherjee S, Wingfield PT, Jaroniec CP, Hinnebusch AG (2010) Activator Gcn4 employs multiple segments of Med15/Gal11, including the KIX domain, to recruit mediator to target genes in vivo. J Biol Chem 285:2438–2455

    Article  PubMed  CAS  Google Scholar 

  53. Milbradt AG, Kulkarni M, Yi T, Takeuchi K, Sun ZY, Luna RE, Selenko P, Naar AM, Wagner G (2011) Structure of the VP16 transactivator target in the mediator. Nat Struct Mol Biol 18:410–415

    Article  PubMed  CAS  Google Scholar 

  54. Ansari SA, He Q, Morse RH (2009) Mediator complex association with constitutively transcribed genes in yeast. Proc Natl Acad Sci USA 106:16734–16739

    Article  PubMed  CAS  Google Scholar 

  55. Koh SS, Ansari AZ, Ptashne M, Young RA (1998) An activator target in the RNA polymerase II holoenzyme. Mol Cell 1:895–904

    Article  PubMed  CAS  Google Scholar 

  56. Fondell JD, Ge H, Roeder RG (1996) Ligand induction of a transcriptionally active thyroid hormone receptor coactivator complex. Proc Natl Acad Sci USA 93:8329–8333

    Article  PubMed  CAS  Google Scholar 

  57. Rachez C, Suldan Z, Ward J, Chang CP, Burakov D, Erdjument-Bromage H, Tempst P, Freedman LP (1998) A novel protein complex that interacts with the vitamin D3 receptor in a ligand-dependent manner and enhances VDR transactivation in a cell-free system. Genes Dev 12:1787–1800

    Article  PubMed  CAS  Google Scholar 

  58. Roeder RG (1996) The role of general initiation factors in transcription by RNA polymerase II. Trends Biochem Sci 21:327–335

    PubMed  CAS  Google Scholar 

  59. Malik S, Guermah M, Yuan CX, Wu W, Yamamura S, Roeder RG (2004) Structural and functional organization of TRAP220, the TRAP/mediator subunit that is targeted by nuclear receptors. Mol Cell Biol 24:8244–8254

    Article  PubMed  CAS  Google Scholar 

  60. Louvion JF, Havaux-Copf B, Picard D (1993) Fusion of GAL4-VP16 to a steroid-binding domain provides a tool for gratuitous induction of galactose-responsive genes in yeast. Gene 131:129–134

    Article  PubMed  CAS  Google Scholar 

  61. Stafford GA, Morse RH (1998) Mutations in the AF-2/hormone-binding domain of the chimeric activator GAL4.estrogen receptor.VP16 inhibit hormone-dependent transcriptional activation and chromatin remodeling in yeast. J Biol Chem 273:34240–34246

    Article  PubMed  CAS  Google Scholar 

  62. Ge K, Cho YW, Guo H, Hong TB, Guermah M, Ito M, Yu H, Kalkum M, Roeder RG (2008) Alternative mechanisms by which mediator subunit MED1/TRAP220 regulates peroxisome proliferator-activated receptor gamma-stimulated adipogenesis and target gene expression. Mol Cell Biol 28:1081–1091

    Article  PubMed  CAS  Google Scholar 

  63. Chen W, Roeder RG (2011) Mediator-dependent nuclear receptor function. Semin Cell Dev Biol 22:749–758

    Article  PubMed  CAS  Google Scholar 

  64. Grontved L, Madsen MS, Boergesen M, Roeder RG, Mandrup S (2010) MED14 tethers mediator to the N-terminal domain of peroxisome proliferator-activated receptor gamma and is required for full transcriptional activity and adipogenesis. Mol Cell Biol 30:2155–2169

    Article  PubMed  CAS  Google Scholar 

  65. Lariviere L, Seizl M, Cramer P (2012) A structural perspective on mediator function. Curr Opin Cell Biol 24:305–313

    Article  PubMed  CAS  Google Scholar 

  66. Malik S, Wallberg AE, Kang YK, Roeder RG (2002) 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

    Article  PubMed  CAS  Google Scholar 

  67. Hittelman AB, Burakov D, Iniguez-Lluhi JA, Freedman LP, Garabedian MJ (1999) Differential regulation of glucocorticoid receptor transcriptional activation via AF-1-associated proteins. EMBO J 18:5380–5388

    Article  PubMed  CAS  Google Scholar 

  68. Lau JF, Nusinzon I, Burakov D, Freedman LP, Horvath CM (2003) Role of metazoan mediator proteins in interferon-responsive transcription. Mol Cell Biol 23:620–628

    Article  PubMed  CAS  Google Scholar 

  69. Boyer TG, Martin ME, Lees E, Ricciardi RP, Berk AJ (1999) Mammalian Srb/mediator complex is targeted by adenovirus E1A protein. Nature 399:276–279

    Article  PubMed  CAS  Google Scholar 

  70. Rana R, Surapureddi S, Kam W, Ferguson S, Goldstein JA (2011) Med25 is required for RNA polymerase II recruitment to specific promoters, thus regulating xenobiotic and lipid metabolism in human liver. Mol Cell Biol 31:466–481

    Article  PubMed  CAS  Google Scholar 

  71. Yamamoto S, Eletsky A, Szyperski T, Hay J, Ruyechan WT (2009) Analysis of the varicella-zoster virus IE62 N-terminal acidic transactivating domain and its interaction with the human mediator complex. J Virol 83:6300–6305

    Article  PubMed  CAS  Google Scholar 

  72. Yang M, Hay J, Ruyechan WT (2008) Varicella-zoster virus IE62 protein utilizes the human mediator complex in promoter activation. J Virol 82:12154–12163

    Article  PubMed  CAS  Google Scholar 

  73. Backstrom S, Elfving N, Nilsson R, Wingsle G, Bjorklund S (2007) Purification of a plant mediator from Arabidopsis thaliana identifies PFT1 as the Med25 subunit. Mol Cell 26:717–729

    Article  PubMed  CAS  Google Scholar 

  74. Autran D, Jonak C, Belcram K, Beemster GT, Kronenberger J, Grandjean O, Inze D, Traas J (2002) Cell numbers and leaf development in Arabidopsis: a functional analysis of the STRUWWELPETER gene. EMBO J 21:6036–6049

    Article  PubMed  CAS  Google Scholar 

  75. Wang W, Chen X (2004) HUA ENHANCER3 reveals a role for a cyclin-dependent protein kinase in the specification of floral organ identity in Arabidopsis. Development 131:3147–3156

    Article  PubMed  CAS  Google Scholar 

  76. Kidd BN, Cahill DM, Manners JM, Schenk PM, Kazan K (2011) Diverse roles of the mediator complex in plants. Semin Cell Dev Biol 22:741–748

    Article  PubMed  CAS  Google Scholar 

  77. Cerdan PD, Chory J (2003) Regulation of flowering time by light quality. Nature 423:881–885

    Article  PubMed  CAS  Google Scholar 

  78. Xu R, Li Y (2011) Control of final organ size by mediator complex subunit 25 in Arabidopsis thaliana. Development 138:4545–4554

    Article  PubMed  CAS  Google Scholar 

  79. Elfving N, Davoine C, Benlloch R, Blomberg J, Brannstrom K, Muller D, Nilsson A, Ulfstedt M, Ronne H, Wingsle G, Nilsson O, Bjorklund S (2011) The Arabidopsis thaliana Med25 mediator subunit integrates environmental cues to control plant development. Proc Natl Acad Sci USA 108:8245–8250

    Article  PubMed  CAS  Google Scholar 

  80. Kidd BN, Edgar CI, Kumar KK, Aitken EA, Schenk PM, Manners JM, Kazan K (2009) The mediator complex subunit PFT1 is a key regulator of jasmonate-dependent defense in Arabidopsis. Plant Cell 21:2237–2252

    Article  PubMed  CAS  Google Scholar 

  81. Cevik V, Kidd BN, Zhang P, Hill C, Kiddle S, Denby KJ, Holub EB, Cahill DM, Manners JM, Schenk PM, Beynon J, Kazan K (2012) MEDIATOR25 acts as an integrative hub for the regulation of jasmonate-responsive gene expression in Arabidopsis. Plant Physiol 160:541–555

    Article  PubMed  CAS  Google Scholar 

  82. Chen R, Jiang H, Li L, Zhai Q, Qi L, Zhou W, Liu X, Li H, Zheng W, Sun J, Li C (2012) The Arabidopsis mediator subunit MED25 differentially regulates jasmonate and abscisic acid signaling through interacting with the MYC2 and ABI5 transcription factors. Plant Cell 24:2898–2916

    Article  PubMed  CAS  Google Scholar 

  83. Koschubs T, Seizl M, Lariviere L, Kurth F, Baumli S, Martin DE, Cramer P (2009) Identification, structure, and functional requirement of the mediator submodule Med7 N/31. EMBO J 28:69–80

    Article  PubMed  CAS  Google Scholar 

  84. Taatjes DJ, Naar AM, Andel F 3rd, Nogales E, Tjian R (2002) Structure, function, and activator-induced conformations of the CRSP coactivator. Science 295:1058–1062

    Article  PubMed  CAS  Google Scholar 

  85. Taatjes DJ, Schneider-Poetsch T, Tjian R (2004) Distinct conformational states of nuclear receptor-bound CRSP-Med complexes. Nat Struct Mol Biol 11:664–671

    Article  PubMed  CAS  Google Scholar 

  86. Meyer KD, Lin SC, Bernecky C, Gao Y, Taatjes DJ (2010) p53 activates transcription by directing structural shifts in mediator. Nat Struct Mol Biol 17:753–760

    Article  PubMed  CAS  Google Scholar 

  87. Taatjes DJ, Marr MT, Tjian R (2004) Regulatory diversity among metazoan co-activator complexes. Nat Rev Mol Cell Biol 5:403–410

    Article  PubMed  CAS  Google Scholar 

  88. Ebmeier CC, Taatjes DJ (2010) Activator–mediator binding regulates mediator-cofactor interactions. Proc Natl Acad Sci USA 107:11283–11288

    Article  PubMed  CAS  Google Scholar 

  89. Han SJ, Lee YC, Gim BS, Ryu GH, Park SJ, Lane WS, Kim YJ (1999) Activator-specific requirement of yeast mediator proteins for RNA polymerase II transcriptional activation. Mol Cell Biol 19:979–988

    PubMed  CAS  Google Scholar 

  90. Lee YC, Min S, Gim BS, Kim YJ (1997) A transcriptional mediator protein that is required for activation of many RNA polymerase II promoters and is conserved from yeast to humans. Mol Cell Biol 17:4622–4632

    PubMed  CAS  Google Scholar 

  91. Swanson MJ, Qiu H, Sumibcay L, Krueger A, Kim SJ, Natarajan K, Yoon S, Hinnebusch AG (2003) A multiplicity of coactivators is required by Gcn4p at individual promoters in vivo. Mol Cell Biol 23:2800–2820

    Article  PubMed  CAS  Google Scholar 

  92. Imasaki T, Calero G, Cai G, Tsai KL, Yamada K, Cardelli F, Erdjument-Bromage H, Tempst P, Berger I, Kornberg GL, Asturias FJ, Kornberg RD, Takagi Y (2011) Architecture of the mediator head module. Nature 475:240–243

    Article  PubMed  CAS  Google Scholar 

  93. Lorch Y, Beve J, Gustafsson CM, Myers LC, Kornberg RD (2000) Mediator-nucleosome interaction. Mol Cell 6:197–201

    PubMed  CAS  Google Scholar 

  94. Li B, Carey M, Workman JL (2007) The role of chromatin during transcription. Cell 128:707–719

    Article  PubMed  CAS  Google Scholar 

  95. Roeder RG (2005) Transcriptional regulation and the role of diverse coactivators in animal cells. FEBS Lett 579:909–915

    Article  PubMed  CAS  Google Scholar 

  96. Yoon S, Qiu H, Swanson MJ, Hinnebusch AG (2003) Recruitment of SWI/SNF by Gcn4p does not require Snf2p or Gcn5p but depends strongly on SWI/SNF integrity, SRB mediator, and SAGA. Mol Cell Biol 23:8829–8845

    Article  PubMed  CAS  Google Scholar 

  97. Qiu H, Hu C, Zhang F, Hwang GJ, Swanson MJ, Boonchird C, Hinnebusch AG (2005) Interdependent recruitment of SAGA and Srb mediator by transcriptional activator Gcn4p. Mol Cell Biol 25:3461–3474

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  99. Ryan MP, Jones R, Morse RH (1998) SWI-SNF complex participation in transcriptional activation at a step subsequent to activator binding. Mol Cell Biol 18:1774–1782

    PubMed  CAS  Google Scholar 

  100. Sharma VM, Li B, Reese JC (2003) SWI/SNF-dependent chromatin remodeling of RNR3 requires TAF(II)s and the general transcription machinery. Genes Dev 17:502–515

    Article  PubMed  CAS  Google Scholar 

  101. Martens JA, Wu PY, Winston F (2005) Regulation of an intergenic transcript controls adjacent gene transcription in Saccharomyces cerevisiae. Genes Dev 19:2695–2704

    Article  PubMed  CAS  Google Scholar 

  102. He Q, Battistella L, Morse RH (2008) Mediator requirement downstream of chromatin remodeling during transcriptional activation of CHA1 in yeast. J Biol Chem 283:5276–5286

    Article  PubMed  CAS  Google Scholar 

  103. Bhaumik SR, Green MR (2001) SAGA is an essential in vivo target of the yeast acidic activator Gal4p. Genes Dev 15:1935–1945

    Article  PubMed  CAS  Google Scholar 

  104. Larschan E, Winston F (2005) The Saccharomyces cerevisiae Srb8-Srb11 complex functions with the SAGA complex during Gal4-activated transcription. Mol Cell Biol 25:114–123

    Article  PubMed  CAS  Google Scholar 

  105. Bryant GO, Ptashne M (2003) Independent recruitment in vivo by gal4 of two complexes required for transcription. Mol Cell 11:1301–1309

    Article  PubMed  CAS  Google Scholar 

  106. Govind CK, Yoon S, Qiu H, Govind S, Hinnebusch AG (2005) Simultaneous recruitment of coactivators by Gcn4p stimulates multiple steps of transcription in vivo. Mol Cell Biol 25:5626–5638

    Article  PubMed  CAS  Google Scholar 

  107. Liu X, Vorontchikhina M, Wang YL, Faiola F, Martinez E (2008) STAGA recruits mediator to the MYC oncoprotein to stimulate transcription and cell proliferation. Mol Cell Biol 28:108–121

    Article  PubMed  CAS  Google Scholar 

  108. Acevedo ML, Kraus WL (2003) Mediator and p300/CBP-steroid receptor coactivator complexes have distinct roles, but function synergistically, during estrogen receptor alpha-dependent transcription with chromatin templates. Mol Cell Biol 23:335–348

    Article  PubMed  CAS  Google Scholar 

  109. Black JC, Choi JE, Lombardo SR, Carey M (2006) A mechanism for coordinating chromatin modification and preinitiation complex assembly. Mol Cell 23:809–818

    Article  PubMed  CAS  Google Scholar 

  110. Krebs AR, Demmers J, Karmodiya K, Chang NC, Chang AC, Tora L (2010) ATAC and mediator coactivators form a stable complex and regulate a set of non-coding RNA genes. EMBO Rep 11:541–547

    Article  PubMed  CAS  Google Scholar 

  111. Lin JJ, Lehmann LW, Bonora G, Sridharan R, Vashisht AA, Tran N, Plath K, Wohlschlegel JA, Carey M (2011) Mediator coordinates PIC assembly with recruitment of CHD1. Genes Dev 25:2198–2209

    Article  PubMed  CAS  Google Scholar 

  112. Thompson CM, Young RA (1995) General requirement for RNA polymerase II holoenzymes in vivo. Proc Natl Acad Sci USA 92:4587–4590

    Article  PubMed  CAS  Google Scholar 

  113. Holstege FC, Jennings EG, Wyrick JJ, Lee TI, Hengartner CJ, Green MR, Golub TR, Lander ES, Young RA (1998) Dissecting the regulatory circuitry of a eukaryotic genome. Cell 95:717–728

    Article  PubMed  CAS  Google Scholar 

  114. Takagi Y, Kornberg RD (2006) Mediator as a general transcription factor. J Biol Chem 281:80–89

    Article  PubMed  CAS  Google Scholar 

  115. Mittler G, Kremmer E, Timmers HT, Meisterernst M (2001) Novel critical role of a human mediator complex for basal RNA polymerase II transcription. EMBO Rep 2:808–813

    Article  PubMed  CAS  Google Scholar 

  116. Baek HJ, Malik S, Qin J, Roeder RG (2002) Requirement of TRAP/mediator for both activator-independent and activator-dependent transcription in conjunction with TFIID-associated TAF(II)s. Mol Cell Biol 22:2842–2852

    Article  PubMed  CAS  Google Scholar 

  117. Deato MD, Marr MT, Sottero T, Inouye C, Hu P, Tjian R (2008) MyoD targets TAF3/TRF3 to activate myogenin transcription. Mol Cell 32:96–105

    Article  PubMed  CAS  Google Scholar 

  118. Thiaville MM, Dudenhausen EE, Awad KS, Gjymishka A, Zhong C, Kilberg MS (2008) Activated transcription via mammalian amino acid response elements does not require enhanced recruitment of the mediator complex. Nucleic Acids Res 36:5571–5580

    Article  PubMed  CAS  Google Scholar 

  119. Veenstra GJ, Wolffe AP (2001) Gene-selective developmental roles of general transcription factors. Trends Biochem Sci 26:665–671

    Article  PubMed  CAS  Google Scholar 

  120. Conaway RC, Conaway JW (2011) Function and regulation of the mediator complex. Curr Opin Genet Dev 21:225–230

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  122. Uhlmann T, Boeing S, Lehmbacher M, Meisterernst M (2007) The VP16 activation domain establishes an active mediator lacking CDK8 in vivo. J Biol Chem 282:2163–2173

    Article  PubMed  CAS  Google Scholar 

  123. Kim YJ, Bjorklund S, Li Y, Sayre MH, Kornberg RD (1994) A multiprotein mediator of transcriptional activation and its interaction with the C-terminal repeat domain of RNA polymerase II. Cell 77:599–608

    Article  PubMed  CAS  Google Scholar 

  124. Koleske AJ, Young RA (1994) An RNA polymerase II holoenzyme responsive to activators. Nature 368:466–469

    Article  PubMed  CAS  Google Scholar 

  125. Thompson CM, Koleske AJ, Chao DM, Young RA (1993) A multisubunit complex associated with the RNA polymerase II CTD and TATA-binding protein in yeast. Cell 73:1361–1375

    Article  PubMed  CAS  Google Scholar 

  126. Tardiff DF, Abruzzi KC, Rosbash M (2007) Protein characterization of Saccharomyces cerevisiae RNA polymerase II after in vivo cross-linking. Proc Natl Acad Sci USA 104:19948–19953

    Article  PubMed  CAS  Google Scholar 

  127. Davis JA, Takagi Y, Kornberg RD, Asturias FA (2002) Structure of the yeast RNA polymerase II holoenzyme: mediator conformation and polymerase interaction. Mol Cell 10:409–415

    Article  PubMed  CAS  Google Scholar 

  128. Mehta S, Miklos I, Sipiczki M, Sengupta S, Sharma N (2009) The Med8 mediator subunit interacts with the Rpb4 subunit of RNA polymerase II and Ace2 transcriptional activator in Schizosaccharomyces pombe. FEBS Lett 583:3115–3120

    Article  PubMed  CAS  Google Scholar 

  129. Cai G, Imasaki T, Takagi Y, Asturias FJ (2009) Mediator structural conservation and implications for the regulation mechanism. Structure 17:559–567

    Article  PubMed  CAS  Google Scholar 

  130. Wang G, Balamotis MA, Stevens JL, Yamaguchi Y, Handa H, Berk AJ (2005) Mediator requirement for both recruitment and postrecruitment steps in transcription initiation. Mol Cell 17:683–694

    Article  PubMed  CAS  Google Scholar 

  131. Cantin GT, Stevens JL, Berk AJ (2003) Activation domain-mediator interactions promote transcription preinitiation complex assembly on promoter DNA. Proc Natl Acad Sci USA 100:12003–12008

    Article  PubMed  CAS  Google Scholar 

  132. Kuras L, Struhl K (1999) Binding of TBP to promoters in vivo is stimulated by activators and requires Pol II holoenzyme. Nature 399:609–613

    Article  PubMed  CAS  Google Scholar 

  133. Li XY, Virbasius A, Zhu X, Green MR (1999) Enhancement of TBP binding by activators and general transcription factors. Nature 399:605–609

    Article  PubMed  CAS  Google Scholar 

  134. Qiu H, Hu C, Yoon S, Natarajan K, Swanson MJ, Hinnebusch AG (2004) An array of coactivators is required for optimal recruitment of TATA binding protein and RNA polymerase II by promoter-bound Gcn4p. Mol Cell Biol 24:4104–4117

    Article  PubMed  CAS  Google Scholar 

  135. Bhaumik SR, Raha T, Aiello DP, Green MR (2004) In vivo target of a transcriptional activator revealed by fluorescence resonance energy transfer. Genes Dev 18:333–343

    Article  PubMed  CAS  Google Scholar 

  136. Koleske AJ, Buratowski S, Nonet M, Young RA (1992) A novel transcription factor reveals a functional link between the RNA polymerase II CTD and TFIID. Cell 69:883–894

    Article  PubMed  CAS  Google Scholar 

  137. Lariviere L, Geiger S, Hoeppner S, Rother S, Strasser K, Cramer P (2006) Structure and TBP binding of the mediator head subcomplex Med8-Med18-Med20. Nat Struct Mol Biol 13:895–901

    Article  PubMed  CAS  Google Scholar 

  138. Seizl M, Lariviere L, Pfaffeneder T, Wenzeck L, Cramer P (2011) 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

    Article  PubMed  CAS  Google Scholar 

  139. Sakurai H, Fukasawa T (2003) Artificial recruitment of certain mediator components affects requirement of basal transcription factor IIE. Genes Cells 8:41–50

    Article  PubMed  CAS  Google Scholar 

  140. Sakurai H, Fukasawa T (1998) Functional correlation among Gal11, transcription factor (TF) IIE, and TFIIH in Saccharomyces cerevisiae. Gal11 and TFIIE cooperatively enhance TFIIH-mediated phosphorylation of RNA polymerase II carboxyl-terminal domain sequences. J Biol Chem 273:9534–9538

    Article  PubMed  CAS  Google Scholar 

  141. Baek HJ, Kang YK, Roeder RG (2006) Human mediator enhances basal transcription by facilitating recruitment of transcription factor IIB during preinitiation complex assembly. J Biol Chem 281:15172–15181

    Article  PubMed  CAS  Google Scholar 

  142. Guidi BW, Bjornsdottir G, Hopkins DC, Lacomis L, Erdjument-Bromage H, Tempst P, Myers LC (2004) Mutual targeting of mediator and the TFIIH kinase Kin28. J Biol Chem 279:29114–29120

    Article  PubMed  CAS  Google Scholar 

  143. Sogaard TM, Svejstrup JQ (2007) Hyperphosphorylation of the C-terminal repeat domain of RNA polymerase II facilitates dissociation of its complex with mediator. J Biol Chem 282:14113–14120

    Article  PubMed  CAS  Google Scholar 

  144. Akoulitchev S, Chuikov S, Reinberg D (2000) TFIIH is negatively regulated by cdk8-containing mediator complexes. Nature 407:102–106

    Article  PubMed  CAS  Google Scholar 

  145. Jishage M, Malik S, Wagner U, Uberheide B, Ishihama Y, Hu X, Chait BT, Gnatt A, Ren B, Roeder RG (2012) Transcriptional regulation by Pol II(G) involving mediator and competitive interactions of Gdown1 and TFIIF with Pol II. Mol Cell 45:51–63

    Article  PubMed  CAS  Google Scholar 

  146. Cheng B, Li T, Rahl PB, Adamson TE, Loudas NB, Guo J, Varzavand K, Cooper JJ, Hu X, Gnatt A, Young RA, Price DH (2012) Functional association of Gdown1 with RNA polymerase II poised on human genes. Mol Cell 45:38–50

    Article  PubMed  CAS  Google Scholar 

  147. Espinosa JM (2012) Get back TFIIF, don’t let me Gdown1. Mol Cell 45:3–5

    Article  PubMed  CAS  Google Scholar 

  148. Malik S, Barrero MJ, Jones T (2007) Identification of a regulator of transcription elongation as an accessory factor for the human mediator coactivator. Proc Natl Acad Sci USA 104:6182–6187

    Article  PubMed  CAS  Google Scholar 

  149. Singh H, Erkine AM, Kremer SB, Duttweiler HM, Davis DA, Iqbal J, Gross RR, Gross DS (2006) A functional module of yeast mediator that governs the dynamic range of heat-shock gene expression. Genetics 172:2169–2184

    Article  PubMed  CAS  Google Scholar 

  150. Young ET, Yen K, Dombek KM, Law GL, Chang E, Arms E (2009) Snf1-independent, glucose-resistant transcription of Adr1-dependent genes in a mediator mutant of Saccharomyces cerevisiae. Mol Microbiol 74:364–383

    Article  PubMed  CAS  Google Scholar 

  151. Hampsey M (1998) Molecular genetics of the RNA polymerase II general transcriptional machinery. Microbiol Mol Biol Rev 62:465–503

    PubMed  CAS  Google Scholar 

  152. Pavri R, Lewis B, Kim TK, Dilworth FJ, Erdjument-Bromage H, Tempst P, de Murcia G, Evans R, Chambon P, Reinberg D (2005) PARP-1 determines specificity in a retinoid signaling pathway via direct modulation of mediator. Mol Cell 18:83–96

    Article  PubMed  CAS  Google Scholar 

  153. Elmlund H, Baraznenok V, Lindahl M, Samuelsen CO, Koeck PJ, Holmberg S, Hebert H, Gustafsson CM (2006) The cyclin-dependent kinase 8 module sterically blocks mediator interactions with RNA polymerase II. Proc Natl Acad Sci USA 103:15788–15793

    Article  PubMed  CAS  Google Scholar 

  154. Knuesel MT, Meyer KD, Bernecky C, Taatjes DJ (2009) The human CDK8 subcomplex is a molecular switch that controls mediator coactivator function. Genes Dev 23:439–451

    Article  PubMed  CAS  Google Scholar 

  155. Andrau JC, van de Pasch L, Lijnzaad P, Bijma T, Koerkamp MG, van de Peppel J, Werner M, Holstege FC (2006) Genome-wide location of the coactivator mediator: binding without activation and transient Cdk8 interaction on DNA. Mol Cell 22:179–192

    Article  PubMed  CAS  Google Scholar 

  156. Belakavadi M, Fondell JD (2010) Cyclin-dependent kinase 8 positively cooperates with mediator to promote thyroid hormone receptor-dependent transcriptional activation. Mol Cell Biol 30:2437–2448

    Article  PubMed  CAS  Google Scholar 

  157. Donner AJ, Szostek S, Hoover JM, Espinosa JM (2007) CDK8 is a stimulus-specific positive coregulator of p53 target genes. Mol Cell 27:121–133

    Article  PubMed  CAS  Google Scholar 

  158. Meyer KD, Donner AJ, Knuesel MT, York AG, Espinosa JM, Taatjes DJ (2008) Cooperative activity of cdk8 and GCN5L within mediator directs tandem phosphoacetylation of histone H3. EMBO J 27:1447–1457

    PubMed  CAS  Google Scholar 

  159. Kim YJ, Zheng B, Yu Y, Won SY, Mo B, Chen X (2011) The role of mediator in small and long noncoding RNA production in Arabidopsis thaliana. EMBO J 30:814–822

    Article  PubMed  CAS  Google Scholar 

  160. Taatjes DJ (2010) The human mediator complex: a versatile, genome-wide regulator of transcription. Trends Biochem Sci 35:315–322

    Article  PubMed  CAS  Google Scholar 

  161. Hashimoto S, Boissel S, Zarhrate M, Rio M, Munnich A, Egly JM, Colleaux L (2011) MED23 mutation links intellectual disability to dysregulation of immediate early gene expression. Science 333:1161–1163

    Article  PubMed  CAS  Google Scholar 

  162. Makinen N, Mehine M, Tolvanen J, Kaasinen E, Li Y, Lehtonen HJ, Gentile M, Yan J, Enge M, Taipale M, Aavikko M, Katainen R, Virolainen E, Bohling T, Koski TA, Launonen V, Sjoberg J, Taipale J, Vahteristo P, Aaltonen LA (2011) MED12, the mediator complex subunit 12 gene, is mutated at high frequency in uterine leiomyomas. Science 334:252–255

    Article  PubMed  CAS  Google Scholar 

  163. Bourbon HM, Aguilera A, Ansari AZ, Asturias FJ, Berk AJ, Bjorklund S, Blackwell TK, Borggrefe T, Carey M, Carlson M, Conaway JW, Conaway RC, Emmons SW, Fondell JD, Freedman LP, Fukasawa T, Gustafsson CM, Han M, He X, Herman PK, Hinnebusch AG, Holmberg S, Holstege FC, Jaehning JA, Kim YJ, Kuras L, Leutz A, Lis JT, Meisterernest M, Naar AM, Nasmyth K, Parvin JD, Ptashne M, Reinberg D, Ronne H, Sadowski I, Sakurai H, Sipiczki M, Sternberg PW, Stillman DJ, Strich R, Struhl K, Svejstrup JQ, Tuck S, Winston F, Roeder RG, Kornberg RD (2004) A unified nomenclature for protein subunits of mediator complexes linking transcriptional regulators to RNA polymerase II. Mol Cell 14:553–557

    Article  PubMed  CAS  Google Scholar 

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Supported by NSF grant MCB0949722.

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Ansari, S.A., Morse, R.H. Mechanisms of Mediator complex action in transcriptional activation. Cell. Mol. Life Sci. 70, 2743–2756 (2013). https://doi.org/10.1007/s00018-013-1265-9

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