The Mediator complex: A central integrator of transcription

Nature Reviews Molecular Cell Biology

Volumn 16, Issue 3, 2015, Pages 155-166

  Allen, Benjamin L ^a   Taatjes, Dylan J ^a  

^a UNIVERSITY OF COLORADO   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYCLIN DEPENDENT KINASE 8; MEDIATOR COMPLEX; RNA POLYMERASE II; CHROMATIN; HISTONE; TRANSCRIPTION FACTOR; UNTRANSLATED RNA;

CHROMATIN STRUCTURE; EUKARYOTE; MOLECULAR DYNAMICS; PRIORITY JOURNAL; PROTEIN CONFORMATION; PROTEIN SUBUNIT; REVIEW; RNA GENE; TRANSCRIPTION INITIATION; TRANSCRIPTION REGULATION; ANIMAL; CHEMISTRY; CHROMATIN; FEMALE; GENE EXPRESSION REGULATION; GENETIC TRANSCRIPTION; GENETICS; HUMAN; LEIOMYOMA; METABOLISM; PATHOLOGY; SIGNAL TRANSDUCTION; UTERUS CANCER;

EUKARYOTA; METAZOA;

ANIMALS; CHROMATIN; FEMALE; GENE EXPRESSION REGULATION; HISTONES; HUMANS; LEIOMYOMA; MEDIATOR COMPLEX; RNA POLYMERASE II; RNA, UNTRANSLATED; SIGNAL TRANSDUCTION; TRANSCRIPTION FACTORS; TRANSCRIPTION, GENETIC; UTERINE NEOPLASMS;

EID: 84923811117     PISSN: 14710072     EISSN: 14710080     Source Type: Journal    
DOI: 10.1038/nrm3951     Document Type: Review

References (198)

1. Plank, J. L. & Dean, A. Enhancer function: mechanistic and genome-wide insights come together. Mol. Cell 55, 5-14 (2014).
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).
3. Ansari, S. A. & Morse, R. H. Mechanisms of Mediator complex action in transcriptional activation. Cell. Mol. Life Sci. 70, 2743-2756 (2013).
4. Xu, W. & Ji, J. Y. Dysregulation of CDK8 and Cyclin C in tumorigenesis. J. Genet. Genom. 38, 439-452 (2011).
5. Spaeth, J. M., Kim, N. H. & Boyer, T. G. Mediator and human disease. Semin. Cell Dev. Biol. 22, 776-787 (2011).
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).
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).
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).
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).
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).
11. Stevens, J. L. et al. Transcription control by E1A and MAP kinase pathway via Sur2 mediator subunit. Science 296, 755-758 (2002).
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).
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).
14. Deato, M. D. E. et al. MyoD targets TAF3/TRF3 to activate Myogenin transcription. Mol. Cell 32, 96-105 (2008).
15. Herrera, F. J., Yamaguchi, T., Roelink, H. & Tjian, R. Core promoter factor TAF9B regulates neuronal gene expression. Elife 3, e02559 (2014).
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).
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).
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).
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).
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).
21. Barbieri, C. E. et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nature Genet. 44, 685-689 (2012).
22. Li, N. et al. Cyclin C is a haploinsufficient tumour suppressor. Nature Cell Biol. 16, 1080-1091 (2014).
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).
24. Risheg, H. et al. A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome. Nature Genet. 39, 451-453 (2007).
25. Ding, N. et al. Mediator links epigenetic silencing of neuronal gene expression with X-linked mental retardation. Mol. Cell 31, 347-359 (2008).
26. Turunen, M. et al. Uterine leiomyoma-linked MED12 mutations disrupt mediator-associated CDK activity. Cell Rep. 7, 654-660 (2014).
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).
28. Galbraith, M. D. et al. HIF1A employs CDK8-Mediator to stimulate RNAPII elongation in response to hypoxia. Cell 153, 1327-1339 (2013).
29. Alarcon, C. et al. Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-pathways. Cell 139, 757-769 (2009).
30. Bancerek, J. et al. CDK8 kinase phosphorylates transcription factor STAT1 to selectively regulate the interferon response. Immunity 38, 250-262 (2013).
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).
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).
33. Morris, E. J. et al. E2F1 represses-catenin transcription and is antagonized by both pRB and CDK8. Nature 455, 552-556 (2008).
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).
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).
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).
38. Toth-Petroczy, A. et al. Malleable machines in transcription regulation: the mediator complex. PLoS Comput. Biol. 4, e1000243 (2008).
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).
40. Cai, G., Imasaki, T., Takagi, Y. & Asturias, F. A. Mediator structural conservation and implications for the regulation mechanism. Structure 17, 559-567 (2009).
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).
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).
43. Ebmeier, C. C. & Taatjes, D. J. Activator-Mediator binding regulates Mediator-cofactor interactions. Proc. Natl Acad. Sci. USA 107, 11283-11288 (2010).
44. Tsai, K. L. et al. Subunit architecture and functional modular rearrangements of the transcriptional mediator complex. Cell 157, 1430-1444 (2014).
45. Wang, X. et al. Redefining the modular organization of the core Mediator complex. Cell Res. 24, 796-808 (2014).
46. Dotson, M. R. et al. Structural organization of yeast and mammalian mediator complexes. Proc. Natl Acad. Sci. USA 97, 14307-14310 (2000).
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).
48. Sakurai, H. & Fukasawa, T. Functional connections between mediator components and general transcription factors of Saccharomyces cerevisiae. J. Biol. Chem. 275, 37251-37256 (2000).
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).
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).
51. Lim, M. K. et al. Gal11p dosage-compensates transcriptional activator deletions via Taf14p. J. Mol. Biol. 374, 9-23 (2007).
52. Guglielmi, B. et al. A high resolution protein interaction map of the yeast Mediator complex. Nucleic Acids Res. 32, 5379-5391 (2004).
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).
54. Imasaki, T. et al. Architecture of the Mediator head module. Nature 475, 240-243 (2011).
55. Lariviere, L. et al. Model of the Mediator middle module based on protein cross-linking. Nucleic Acids Res. 41, 9266-9273 (2013).
56. Lariviere, L. et al. Structure of the Mediator head module. Nature 492, 448-451 (2012).
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).
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).
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).
60. Holstege, F. C. et al. Dissecting the regulatory circuitry of a eukaryotic genome. Cell 95, 717-728 (1998).
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).
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).
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).
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).
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).
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).
67. Marr, M. T., Isogai, Y., Wright, K. J. & Tjian, R. Coactivator cross-talk specifies transcriptional output. Genes Dev. 20, 1458-1469 (2006).
68. Takahashi, H. et al. Human Mediator subunit MED26 functions as a docking site for transcription elongation factors. Cell 146, 92-104 (2011).
69. Xu, M. et al. Core promoter-selective function of HMGA1 and Mediator in Initiator-dependent transcription. Genes Dev. 25, 2513-2524 (2011).
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).
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).
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).
73. Esnault, C. et al. Mediator-dependent recruitment of TFIIH modules in Preinitiation Complex. Mol. Cell 31, 337-346 (2008).
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).
75. Hu, X. et al. A Mediator-responsive form of metazoan RNA polymerase II. Proc. Natl Acad. Sci. USA 103, 9506-9511 (2006).
76. Cheng, B. et al. Functional association of Gdown1 with RNA polymerase II poised on human genes. Mol. Cell 45, 38-50 (2012).
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).
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).
79. Corden, J. L. RNA polymerase II C-terminal domain: tethering transcription to transcript and template. Chem. Rev. 113, 8423-8455 (2013).
80. Eick, D. & Geyer, M. The RNA polymerase II carboxy-terminal domain (CTD) code. Chem. Rev. 113, 8456-8490 (2013).
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).
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).
83. Jeronimo, C. & Robert, F. Kin28 regulates the transient association of Mediator with core promoters. Nature Struct. Mol. Biol. 21, 449-455 (2014).
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).
85. Rhee, H. S. & Pugh, B. F. Genome-wide structure and organization of eukaryotic pre-initiation complexes. Nature 483, 295-301 (2012).
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).
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).
88. Seila, A. C. et al. Divergent transcription from active promoters. Science 322, 1849-1851 (2008).
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).
90. Muse, G. W. et al. RNA polymerase is poised for activation across the genome. Nature Genet. 39, 1507-1511 (2007).
91. Zeitlinger, J. et al. RNA polymerase stalling at developmental control genes in the Drosophila melanogaster embryo. Nature Genet. 39, 1512-1516 (2007).
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).
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).
94. Wang, G. et al. Mediator requirement for both recruitment and postrecruitment steps in transcription initiation. Mol. Cell 17, 683-694 (2005).
95. Adelman, K. & Lis, J. T. Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans. Nature Rev. Genet. 13, 720-731 (2012).
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).
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).
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).
99. Balamotis, M. A. et al. Complexity in transcription control at the activation domain-Mediator interface. Sci. Signal. 2, ra20 (2009).
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).
101. Schaaf, C. A. et al. Genome-wide control of RNA polymerase II activity by cohesin. PLoS Genet. 9, e1003382 (2013).
102. Kagey, M. et al. Mediator and cohesin connect gene expression and chromatin architecture. Nature 467, 430-435 (2010).
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).
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).
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).
106. Nock, A., Ascano, J. M., Barrero, M. J. & Malik, S. Mediator-regulated transcription through the +1 nucleosome. Mol. Cell 48, 837-848 (2012).
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).
108. Larson, D. R. et al. Direct observation of frequency modulated transcription in single cells using light activation. ELife 2, e00750 (2013).
109. Sandaltzopoulos, R. & Becker, P. B. Heat shock factor increases the reinitiation rate from potentiated chromatin templates. Mol. Cell. Biol. 18, 361-367 (1998).
110. Yudkovsky, N., Ranish, J. A. & Hahn, S. A transcription reinitiation intermediate that is stabilized by activator. Nature 408, 225-229 (2000).
111. Reid, G. et al. Cyclic, proteasome-mediated turnover of unliganded and liganded ER on responsive promoters is an integral feature of estrogen signaling. Mol. Cell 11, 695-707 (2003).
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).
113. Mo, X., Kowenz-Leutz, E., Xu, H. & Leutz, A. Ras induces mediator complex exchange on C/EBPb. Mol. Cell 13, 241-250 (2004).
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).
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).
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).
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).
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).
119. Lin, J. J. et al. Mediator coordinates PIC assembly with recruitment of CHD1. Genes Dev. 25, 2198-2209 (2011).
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).
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).
122. Levine, M., Cattoglio, C. & Tjian, R. Looping back to leap forward: transcription enters a new era. Cell 157, 13-25 (2014).
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).
124. Li, G. et al. Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell 148, 84-98 (2012).
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).
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).
127. Sanyal, A., Lajoie, B. R., Jain, G. & Dekker, J. The long-range interaction landscape of gene promoters. Nature 489, 109-113 (2012).
128. Phillips-Cremins, J. E. et al. Architectural protein subclasses shape 3D organization of genomes during lineage commitment. Cell 153, 1281-1295 (2013).
129. Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934-947 (2013).
130. Muto, A. et al. Nipbl and Mediator cooperatively regulate gene expression to control limb development. PLoS Genet. 10, e1004671 (2014).
131. Dobi, K. C. & Winston, F. Analysis of transcriptional activation at a distance in Saccharomyces cerevisiae. Mol. Cell. Biol. 27, 5575-5586 (2007).
132. Mukundan, B. & Ansari, A. Srb5/Med18-mediated termination of transcription is dependent on gene looping. J. Biol. Chem. 288, 11384-11394 (2013).
133. Orom, U. A. et al. Long noncoding RNAs with enhancer-like function in human cells. Cell 143, 46-58 (2010).
134. Lai, F. et al. Activating RNAs associate with Mediator to enhance chromatin architecture and transcription. Nature 494, 497-501 (2013).
135. Wang, D. et al. Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature 474, 390-394 (2011).
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).
137. Lam, M. T. et al. Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription. Nature 498, 511-515 (2013).
138. Li, W. et al. Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature 498, 516-520 (2013).
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).
140. Step, S. E. et al. Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPAR-driven enhancers. Genes Dev. 28, 1018-1028 (2014).
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).
142. Gerber, H. P. et al. RNA polymerase II C-terminal domain required for enhancer-driven transcription. Nature 374, 660-662 (1995).
143. Oya, E. et al. Mediator directs co-transcriptional heterochromatin assembly by RNA interference-dependent and-independent pathways. PLoS Genet. 9, e1003677 (2013).
144. Carlsten, J. O. et al. Mediator promotes CENP-a incorporation at fission yeast centromeres. Mol. Cell. Biol. 32, 4035-4043 (2012).
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).
146. Lenstra, T. L. et al. The specificity and topology of chromatin interaction pathways in yeast. Mol. Cell 42, 536-549 (2011).
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).
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).
149. Zhu, X. et al. Mediator influences telomeric silencing and cellular life span. Mol. Cell. Biol. 31, 2413-2421 (2011).
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).
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).
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).
153. Gaarenstroom, T. & Hill, C. S. TGF-signaling to chromatin: how SMADs regulate transcription during self-renewal and differentiation. Semin. Cell Dev. Biol. 32, 107-118 (2014).
154. Kato, Y., Habas, R., Katsuyama, Y., Naar, A. & He, X. A component of the ARC/Mediator complex required for TGF/Nodal signalling. Nature 418, 641-646 (2002).
155. Zhao, M. et al. Mediator MED15 modulates transforming growth factor (TGF)/Smad signaling and breast cancer cell metastasis. J. Mol. Cell. Biol. 5, 57-60 (2013).
156. Huang, S. et al. MED12 controls the response to multiple cancer drugs through regulation of TGF-receptor signaling. Cell 151, 937-950 (2012).
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).
158. Gao, S. et al. Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGF-signaling. Mol. Cell 36, 457-468 (2009).
159. Kahn, M. Can we safely target the WNT pathway Nature Rev. Drug Discov. 13, 513-532 (2014).
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).
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).
162. Kim, S., Xu, X., Hecht, A. & Boyer, T. G. Mediator is a transducer of Wnt/-catenin signaling. J. Biol. Chem. 281, 14066-14075 (2006).
163. Zhang, H. & Emmons, S. W. AC. elegans mediator protein confers regulatory selectivity on lineage-specific expression of a transcription factor gene. Genes Dev. 14, 2161-2172 (2000).
164. Zhao, J., Ramos, R. & Demma, M. CDK8 regulates E2F1 transcriptional activity through S375 phosphorylation. Oncogene 32, 3520-3530 (2012).
165. Firestein, R. et al. CDK8 is a colorectal cancer oncogene that regulates-catenin activity. Nature 455, 547-551 (2008).
166. Kasza, A. Signal-dependent Elk-1 target genes involved in transcript processing and cell migration. Biochim. Biophys. Acta 1829, 1026-1033 (2013).
167. Wang, W. et al. Mediator MED23 links insulin signaling to the adipogenesis transcription cascade. Dev. Cell 16, 764-771 (2009).
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).
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).
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).
171. Papantonis, A. & Cook, P. R. Transcription factories: genome organization and gene regulation. Chem. Rev. 113, 8683-8705 (2013).
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).
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).
174. Tompa, P. Hydrogel formation by multivalent IDPs: a reincarnation of the microtrabecular lattice Intrinsically Disordered Proteins 1, e24068 (2013).
175. Takagi, Y. & Kornberg, R. D. Mediator as a general transcription factor. J. Biol. Chem. 281, 80-89 (2006).
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).
177. van der Lee, R. et al. Classification of intrinsically disordered regions and proteins. Chem. Rev. 114, 6589-6631 (2014).
178. Madhani, H. D. The frustrated gene: origins of eukaryotic gene expression. Cell 155, 744-749 (2013).
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).
180. Napoli, C., Sessa, M., Infante, T. & Casamassimi, A. Unraveling framework of the ancestral Mediator complex in human diseases. Biochimie 94, 579-587 (2012).
181. Phillips, A. J. & Taatjes, D. J. Small molecule probes to target the human Mediator complex. Isr. J. Chem. 53, 588-595 (2013).
182. Milbradt, A. G. et al. Structure of the VP16 transactivator target in the Mediator. Nature Struct. Mol. Biol. 18, 410-415 (2011).
183. Vojnic, E. et al. Structure and VP16 binding of the Mediator Med25 activator interaction domain. Nature Struct. Mol. Biol. 18, 404-409 (2011).
184. Yang, F. et al. An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis. Nature 442, 700-704 (2006).
185. Loven, J. et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153, 320-334 (2013).
186. Whyte, W. A. et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153, 307-319 (2013).
187. Gerstein, M. B. et al. Integrative analysis of the Caenorhabditis elegans genome by the modENCODE project. Science 330, 1775-1787 (2010).
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).
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).
191. Grunberg, S. & Hahn, S. Structural insights into transcription initiation by RNA polymerase II. Trends Biochem. Sci. 38, 603-611 (2013).
192. Thomas, M. C. & Chiang, C. M. The general transcription machinery and general cofactors. Crit. Rev. Biochem. Mol. Biol. 41, 105-178 (2006).
193. He, Y., Fang, J., Taatjes, D. J. & Nogales, E. Structural visualization of key steps in human transcription initiation. Nature 495, 481-486 (2013).
194. Murakami, K. et al. Architecture of an RNA polymerase II transcription pre-initiation complex. Science 342, 1238724 (2013).
195. Muhlbacher, W. et al. Conserved architecture of the core RNA polymerase II initiation complex. Nature Commun. 5, 4310 (2014).
196. Bieniossek, C. et al. The architecture of human general transcription factor TFIID core complex. Nature 493, 699-702 (2013).
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).
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).