The Mediator complex as a master regulator of transcription by RNA polymerase II.
Journal
Nature reviews. Molecular cell biology
ISSN: 1471-0080
Titre abrégé: Nat Rev Mol Cell Biol
Pays: England
ID NLM: 100962782
Informations de publication
Date de publication:
11 2022
11 2022
Historique:
accepted:
17
05
2022
pubmed:
22
6
2022
medline:
26
10
2022
entrez:
21
6
2022
Statut:
ppublish
Résumé
The Mediator complex, which in humans is 1.4 MDa in size and includes 26 subunits, controls many aspects of RNA polymerase II (Pol II) function. Apart from its size, a defining feature of Mediator is its intrinsic disorder and conformational flexibility, which contributes to its ability to undergo phase separation and to interact with a myriad of regulatory factors. In this Review, we discuss Mediator structure and function, with emphasis on recent cryogenic electron microscopy data of the 4.0-MDa transcription preinitiation complex. We further discuss how Mediator and sequence-specific DNA-binding transcription factors enable enhancer-dependent regulation of Pol II function at distal gene promoters, through the formation of molecular condensates (or transcription hubs) and chromatin loops. Mediator regulation of Pol II reinitiation is also discussed, in the context of transcription bursting. We propose a working model for Mediator function that combines experimental results and theoretical considerations related to enhancer-promoter interactions, which reconciles contradictory data regarding whether enhancer-promoter communication is direct or indirect. We conclude with a discussion of Mediator's potential as a therapeutic target and of future research directions.
Identifiants
pubmed: 35725906
doi: 10.1038/s41580-022-00498-3
pii: 10.1038/s41580-022-00498-3
pmc: PMC9207880
doi:
Substances chimiques
RNA Polymerase II
EC 2.7.7.-
Mediator Complex
0
Transcription Factors
0
Chromatin
0
DNA
9007-49-2
Types de publication
Journal Article
Review
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
732-749Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM139550
Pays : United States
Informations de copyright
© 2022. Springer Nature Limited.
Références
Mol Cell Biol. 2006 Dec;26(23):8667-82
pubmed: 17000779
Science. 2022 Feb 4;375(6580):566-570
pubmed: 35113722
Elife. 2019 May 24;8:
pubmed: 31124784
Nat Commun. 2020 Nov 12;11(1):5736
pubmed: 33184256
J Biol Chem. 1987 Mar 15;262(8):3452-61
pubmed: 2434502
Proc Natl Acad Sci U S A. 2021 Feb 9;118(6):
pubmed: 33542097
Dev Cell. 2009 May;16(5):764-71
pubmed: 19460352
Mol Cell Biol. 2010 May;30(9):2155-69
pubmed: 20194623
Mol Cell. 2021 Apr 15;81(8):1781-1788.e4
pubmed: 33571424
Annu Rev Biochem. 2021 Jun 20;90:193-219
pubmed: 34153211
EMBO J. 2021 May 3;40(9):e107015
pubmed: 33555055
Nature. 2021 Jun;594(7861):124-128
pubmed: 33902107
Proc Natl Acad Sci U S A. 2006 Dec 12;103(50):18928-33
pubmed: 17138671
Nat Struct Mol Biol. 2020 Nov;27(11):1032-1040
pubmed: 32958948
Genome Res. 2019 Apr;29(4):602-612
pubmed: 30796039
Nature. 2019 Aug;572(7770):543-548
pubmed: 31391587
Nat Commun. 2020 Feb 26;11(1):1063
pubmed: 32102997
Cell. 1994 May 20;77(4):599-608
pubmed: 8187178
Nat Struct Mol Biol. 2010 Jun;17(6):753-60
pubmed: 20453859
Mol Cell. 2004 Nov 19;16(4):509-20
pubmed: 15546612
J Clin Invest. 2012 Jul;122(7):2417-27
pubmed: 22684109
Mol Cell. 2020 Dec 3;80(5):845-861.e10
pubmed: 33232656
Elife. 2018 Dec 12;7:
pubmed: 30540252
Cell. 2021 May 27;184(11):3022-3040.e28
pubmed: 33961781
Nat Struct Mol Biol. 2011 Apr;18(4):410-5
pubmed: 21378963
Nature. 2017 Nov 9;551(7679):204-209
pubmed: 29088706
Nature. 2011 Jul 03;475(7355):240-3
pubmed: 21725323
Mol Cell. 2014 May 22;54(4):601-12
pubmed: 24746699
Plant Cell Physiol. 2017 Jan 1;58(1):4-21
pubmed: 28173572
Nat Cell Biol. 2020 Oct;22(10):1223-1238
pubmed: 32989249
PLoS Genet. 2015 Dec 01;11(12):e1005701
pubmed: 26624996
Nat Rev Mol Cell Biol. 2015 Mar;16(3):167-77
pubmed: 25693130
Genes Dev. 2019 Aug 1;33(15-16):960-982
pubmed: 31123063
Genes Dev. 2020 Apr 1;34(7-8):465-488
pubmed: 32238450
PLoS Comput Biol. 2008 Dec;4(12):e1000243
pubmed: 19096501
Nat Commun. 2021 Jul 23;12(1):4504
pubmed: 34301936
Elife. 2015 Sep 24;4:
pubmed: 26402457
Cell. 2019 Jul 11;178(2):491-506.e28
pubmed: 31155237
Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8329-33
pubmed: 8710870
Science. 2018 Jul 27;361(6400):
pubmed: 29930091
Transcription. 2020 Feb;11(1):3-18
pubmed: 31856658
Cell. 2014 Dec 18;159(7):1665-80
pubmed: 25497547
Nat Rev Drug Discov. 2021 Oct;20(10):789-797
pubmed: 34285415
Oncotarget. 2016 Apr 26;7(17):23043-23055
pubmed: 27050271
Elife. 2018 Feb 09;7:
pubmed: 29424691
Proc Natl Acad Sci U S A. 2019 Jul 23;116(30):15062-15067
pubmed: 31285341
Nature. 2010 Sep 23;467(7314):430-5
pubmed: 20720539
Science. 2019 Sep 6;365(6457):
pubmed: 31488662
Mol Cell. 2003 Nov;12(5):1137-49
pubmed: 14636573
J Am Chem Soc. 2021 Jun 30;143(25):9297-9302
pubmed: 34137598
J Mol Biol. 2021 Jul 9;433(14):167016
pubmed: 33951451
Nat Rev Mol Cell Biol. 2015 Mar;16(3):144-54
pubmed: 25650801
Elife. 2015 Aug 28;4:
pubmed: 26314865
J Biol Chem. 2002 Nov 8;277(45):42852-8
pubmed: 12218053
Cell. 2018 Nov 29;175(6):1481-1491.e13
pubmed: 30500535
Genes Dev. 2021 Aug 1;35(15-16):1175-1189
pubmed: 34301767
Genes Dev. 1999 Jan 1;13(1):49-63
pubmed: 9887099
Nature. 2012 Dec 20;492(7429):448-51
pubmed: 23123849
Mol Cell. 2020 Aug 6;79(3):459-471.e4
pubmed: 32553192
Cell. 2016 Sep 8;166(6):1411-1422.e16
pubmed: 27610567
Nature. 2015 Feb 19;518(7539):376-80
pubmed: 25652824
Science. 2021 Jun 4;372(6546):
pubmed: 33958484
Science. 2021 Apr 30;372(6541):
pubmed: 33795473
Development. 2010 Aug;137(16):2723-31
pubmed: 20630950
Nat Commun. 2016 Jul 27;7:12248
pubmed: 27461529
Cell Rep. 2022 Apr 5;39(1):110630
pubmed: 35385747
J Biol Chem. 2021 Jul;297(1):100791
pubmed: 34015334
Mol Cell. 1999 Mar;3(3):361-70
pubmed: 10198638
Genes Dev. 2002 Jul 15;16(14):1852-63
pubmed: 12130544
Mol Cell Biol. 2009 Feb;29(3):650-61
pubmed: 19047373
Nucleic Acids Res. 2013 May;41(9):4847-59
pubmed: 23531547
Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):7939-44
pubmed: 9653119
J Biol Chem. 2016 Dec 23;291(52):26886-26898
pubmed: 27821593
Dev Biol. 2016 Nov 1;419(1):7-18
pubmed: 27287881
Nat Genet. 2020 Jul;52(7):719-727
pubmed: 32483291
J Mol Biol. 2017 Oct 13;429(20):3043-3055
pubmed: 28893534
Mol Cell. 2016 Apr 21;62(2):237-247
pubmed: 27067601
Clin Cancer Res. 2017 Apr 1;23(7):1829-1840
pubmed: 27678455
Cell. 2018 Dec 13;175(7):1842-1855.e16
pubmed: 30449618
Nat Rev Mol Cell Biol. 2021 Oct;22(10):653-670
pubmed: 34341548
Mol Cell. 2022 Feb 3;82(3):677-695.e7
pubmed: 35016035
Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8538-43
pubmed: 9671713
Nat Commun. 2021 Mar 1;12(1):1355
pubmed: 33649303
Nat Genet. 2021 Jul;53(7):1036-1049
pubmed: 34183853
Proc Natl Acad Sci U S A. 2015 Mar 31;112(13):3961-6
pubmed: 25775526
PLoS Genet. 2021 Aug 12;17(8):e1009529
pubmed: 34383744
Cell. 2019 Jan 10;176(1-2):213-226.e18
pubmed: 30554876
Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11283-8
pubmed: 20534441
Nat Genet. 2018 Sep;50(9):1296-1303
pubmed: 30038397
Cell. 2012 Jun 8;149(6):1233-44
pubmed: 22682246
Nature. 2019 Jan;565(7738):251-254
pubmed: 30602787
Curr Opin Chem Biol. 2019 Dec;53:118-124
pubmed: 31586479
Cell. 2014 Jun 5;157(6):1430-1444
pubmed: 24882805
Cell. 2016 Jul 14;166(2):358-368
pubmed: 27293191
Nat Struct Mol Biol. 2014 May;21(5):449-55
pubmed: 24704787
Nature. 1999 Apr 29;398(6730):828-32
pubmed: 10235267
Nat Struct Mol Biol. 2013 May;20(5):611-9
pubmed: 23563140
Mol Cell. 2005 Mar 4;17(5):683-94
pubmed: 15749018
Nat Genet. 2019 Aug;51(8):1272-1282
pubmed: 31308546
Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12003-8
pubmed: 14506297
Cell. 2013 Nov 7;155(4):934-47
pubmed: 24119843
Elife. 2021 Jun 09;10:
pubmed: 34106049
Science. 2018 Jul 27;361(6400):412-415
pubmed: 29930094
Proc Natl Acad Sci U S A. 2012 Oct 9;109(41):E2813-22
pubmed: 22988093
Mol Cell. 2022 Feb 3;82(3):514-526
pubmed: 34863368
Cell. 2014 Nov 20;159(5):1126-1139
pubmed: 25416950
Nat Struct Mol Biol. 2011 Apr;18(4):404-9
pubmed: 21378965
EMBO J. 1999 Oct 1;18(19):5380-8
pubmed: 10508170
Mol Cell. 2019 Feb 7;73(3):519-532.e4
pubmed: 30554946
Trends Biochem Sci. 2021 Jan;46(1):41-50
pubmed: 32917506
Cell. 2013 Mar 14;152(6):1237-51
pubmed: 23498934
Nature. 2015 Oct 8;526(7572):273-276
pubmed: 26416749
Biochemistry. 2006 Jun 6;45(22):6873-88
pubmed: 16734424
Cell. 2013 Apr 11;153(2):320-34
pubmed: 23582323
Proc Natl Acad Sci U S A. 2020 Dec 15;117(50):31614-31622
pubmed: 33268497
Mol Cell. 2022 Jun 2;82(11):2084-2097.e5
pubmed: 35483357
Cell. 2014 Oct 9;159(2):374-387
pubmed: 25303531
Elife. 2018 May 29;7:
pubmed: 29809150
Cell. 2021 Jan 7;184(1):120-132.e14
pubmed: 33382968
Mol Cell. 2008 Aug 8;31(3):347-59
pubmed: 18691967
Proc Natl Acad Sci U S A. 2006 Oct 24;103(43):15788-93
pubmed: 17043218
Mol Cell Biol. 2007 Sep;27(17):6177-82
pubmed: 17620419
Nature. 2000 Nov 9;408(6809):225-9
pubmed: 11089979
J Mol Biol. 2018 Aug 3;430(16):2309-2320
pubmed: 29634920
Mol Cell. 2019 Nov 7;76(3):485-499.e8
pubmed: 31495563
Trends Biochem Sci. 2020 Nov;45(11):961-977
pubmed: 32684431
Cell. 2013 Jun 6;153(6):1281-95
pubmed: 23706625
Nature. 2017 Apr 13;544(7649):196-201
pubmed: 28241144
Nature. 2013 Feb 28;494(7438):497-501
pubmed: 23417068
J Biol Chem. 2014 Oct 3;289(40):27665-76
pubmed: 25100719
J Biol Chem. 2013 Apr 19;288(16):11384-94
pubmed: 23476016
Science. 2018 Mar 2;359(6379):1050-1055
pubmed: 29371426
Mol Cell Biol. 2003 Sep;23(17):6229-42
pubmed: 12917344
Cell. 2015 Aug 27;162(5):1016-28
pubmed: 26317468
Nature. 2021 Apr;592(7853):309-314
pubmed: 33692541
Mol Cell. 2019 Dec 5;76(5):753-766.e6
pubmed: 31563432
Cell. 2013 Apr 11;153(2):307-19
pubmed: 23582322
Mol Cell. 2019 Aug 8;75(3):549-561.e7
pubmed: 31398323
EMBO J. 2016 Nov 15;35(22):2435-2446
pubmed: 27797823
Mol Cell Biol. 2019 Mar 19;39(7):
pubmed: 30670567
Cell. 2020 Apr 16;181(2):306-324.e28
pubmed: 32302570
Nature. 1999 May 20;399(6733):276-9
pubmed: 10353252
J Biol Chem. 2013 Sep 6;288(36):26179-26187
pubmed: 23864652
Nat Rev Genet. 2021 Dec;22(12):749-755
pubmed: 34480110
Science. 2018 Sep 28;361(6409):1341-1345
pubmed: 30262496
Genes Dev. 2017 Aug 1;31(15):1535-1548
pubmed: 28887413
Nature. 2021 Jul;595(7865):125-129
pubmed: 34108683
Mol Cell. 2022 May 19;82(10):1878-1893.e10
pubmed: 35537448
Cell. 2013 Nov 21;155(5):1049-1060
pubmed: 24267890
Annu Rev Biochem. 2020 Jun 20;89:189-212
pubmed: 32208766
Proc Natl Acad Sci U S A. 2014 May 20;111(20):7319-24
pubmed: 24778216
Mol Cell Biol. 1998 Jun;18(6):3234-44
pubmed: 9584164
Nature. 2016 Feb 25;530(7591):485-9
pubmed: 26886795
Cell. 2019 Aug 22;178(5):1145-1158.e20
pubmed: 31402173
Science. 2018 Jul 27;361(6400):
pubmed: 29930090
Cell. 1998 Nov 25;95(5):717-28
pubmed: 9845373
J Biol Chem. 2009 Jan 30;284(5):2648-2656
pubmed: 19049968
J Biol Chem. 2018 Mar 30;293(13):4870-4882
pubmed: 29440396
Nat Commun. 2020 Feb 24;11(1):1019
pubmed: 32094355
Science. 2002 Feb 8;295(5557):1058-62
pubmed: 11834832
EMBO J. 2019 Jun 17;38(12):
pubmed: 31101674
Crit Rev Biochem Mol Biol. 2017 Oct;52(5):475-502
pubmed: 28524697
Nucleic Acids Res. 2020 Nov 4;48(19):11199-11213
pubmed: 32990725
J Mol Biol. 2017 Oct 13;429(20):2975-2995
pubmed: 28728983
Nucleic Acids Res. 2016 Feb 29;44(4):1591-612
pubmed: 26590257
Nat Struct Mol Biol. 2014 Dec;21(12):1028-34
pubmed: 25383669
Genes Dev. 2009 Feb 15;23(4):439-51
pubmed: 19240132
Genes Dev. 2006 Jun 1;20(11):1458-69
pubmed: 16751183
Nat Commun. 2016 Apr 01;7:11149
pubmed: 27033977
Nature. 2022 May;605(7911):754-760
pubmed: 35508662
Proc Natl Acad Sci U S A. 2020 Nov 3;117(44):27346-27353
pubmed: 33077600
Sci Adv. 2019 Apr 10;5(4):eaaw1668
pubmed: 30989119
Cell. 2020 Oct 1;183(1):28-45
pubmed: 32976797
Mol Cell. 2017 May 4;66(3):420-435.e5
pubmed: 28475875
Mol Cell. 2013 Jun 6;50(5):711-22
pubmed: 23746353
Mol Cell. 2016 Nov 3;64(3):443-454
pubmed: 27773675
Cell Rep. 2016 Apr 12;15(2):436-50
pubmed: 27050516
J Biol Chem. 2006 May 19;281(20):14066-75
pubmed: 16565090
Elife. 2019 Mar 12;8:
pubmed: 30860024
Nature. 2009 Nov 5;462(7269):58-64
pubmed: 19890323
Elife. 2021 Apr 27;10:
pubmed: 33904398
Mol Cell. 2019 Sep 19;75(6):1161-1177.e11
pubmed: 31421980
Nature. 2017 May 11;545(7653):248-251
pubmed: 28467824
Cell. 2013 Jan 17;152(1-2):120-31
pubmed: 23332750
Mol Cell. 2000 Apr;5(4):683-93
pubmed: 10882104
Mol Cell Biol. 2016 Jun 29;36(14):1943-60
pubmed: 27185874
Nat Rev Mol Cell Biol. 2018 Jul;19(7):464-478
pubmed: 29740129
Cell. 2021 Jan 7;184(1):207-225.e24
pubmed: 33333019
Nature. 2014 Jul 31;511(7511):616-20
pubmed: 25043025
Cell. 2012 Jun 22;149(7):1431-7
pubmed: 22726432
Cell. 2014 Aug 14;158(4):849-860
pubmed: 25126789
Nat Struct Mol Biol. 2010 Feb;17(2):194-201
pubmed: 20098423
Elife. 2016 Jun 23;5:
pubmed: 27336723
Science. 2002 Apr 26;296(5568):755-8
pubmed: 11934987
J Mol Biol. 2022 Jan 15;434(1):167216
pubmed: 34474085
Nature. 2002 Aug 8;418(6898):641-6
pubmed: 12167862
Mol Cell. 2016 Nov 3;64(3):455-466
pubmed: 27773677
J Biol Chem. 1997 Oct 10;272(41):25500-6
pubmed: 9325263
Nature. 2018 Mar 1;555(7694):61-66
pubmed: 29466338
Nature. 2021 Jul;595(7868):596-599
pubmed: 34234347
Proc Natl Acad Sci U S A. 2017 Sep 19;114(38):10208-10213
pubmed: 28855340
J Biol Chem. 2002 Oct 18;277(42):40156-62
pubmed: 12177005
Cell Stem Cell. 2016 Dec 1;19(6):784-799
pubmed: 27570068
Mol Cell. 2012 Feb 24;45(4):459-69
pubmed: 22264826
Nature. 2006 Aug 10;442(7103):700-4
pubmed: 16799563
Nature. 2018 Aug;560(7720):601-606
pubmed: 30135580
Genes Dev. 2017 Nov 1;31(21):2162-2174
pubmed: 29203645
Nat Genet. 2018 Aug;50(8):1151-1160
pubmed: 29988121
Sci Adv. 2021 Jan 15;7(3):
pubmed: 33523904
Cell. 2013 Jun 6;153(6):1327-39
pubmed: 23746844
Mol Cell Biol. 2002 Aug;22(15):5626-37
pubmed: 12101254
Nat Commun. 2021 Apr 13;12(1):2220
pubmed: 33850123
J Mol Biol. 2010 Mar 19;397(1):57-68
pubmed: 20083121
Mol Cell. 2022 Jan 6;82(1):123-139.e7
pubmed: 34910943
Science. 2021 Apr 2;372(6537):52-56
pubmed: 33707221
Cell. 2020 Apr 2;181(1):102-114
pubmed: 31955850
Elife. 2021 Jul 09;10:
pubmed: 34240703
Am J Hum Genet. 2019 Apr 4;104(4):709-720
pubmed: 30905399
Cell. 2009 Nov 13;139(4):757-69
pubmed: 19914168
Cell. 2014 Mar 27;157(1):13-25
pubmed: 24679523
Nat Commun. 2019 Jun 17;10(1):2669
pubmed: 31209209
Nature. 2019 Sep;573(7772):45-54
pubmed: 31462772
J Biol Chem. 2007 May 11;282(19):14113-20
pubmed: 17376774
Nat Struct Mol Biol. 2013 Nov;20(11):1250-7
pubmed: 24077223
Mol Cell. 2021 Sep 2;81(17):3560-3575.e6
pubmed: 34375585
Nature. 2007 Apr 12;446(7137):820-3
pubmed: 17361130
Nat Commun. 2015 Jan 09;6:5941
pubmed: 25575120
Mol Cell. 1999 May;3(5):673-8
pubmed: 10360183
J Phys Chem B. 2013 Oct 24;117(42):13346-56
pubmed: 23875714
Cell. 2021 May 27;184(11):2878-2895.e20
pubmed: 33979654
EMBO J. 2002 Jul 1;21(13):3464-75
pubmed: 12093747
Science. 2020 Jun 19;368(6497):1386-1392
pubmed: 32554597
Genes Dev. 2017 Jul 1;31(13):1289-1301
pubmed: 28808065
Nature. 2021 Jun;594(7861):129-133
pubmed: 33902108
Cell. 2011 Jul 8;146(1):92-104
pubmed: 21729782
Genes Dev. 2001 May 1;15(9):1078-92
pubmed: 11331604
Nature. 2012 Sep 6;489(7414):109-13
pubmed: 22955621
Cells. 2019 Aug 03;8(8):
pubmed: 31382571
Mol Cell Biol. 2008 Jun;28(11):3573-88
pubmed: 18378697
Science. 2018 Dec 21;362(6421):
pubmed: 30442764
Cell. 2018 Feb 8;172(4):650-665
pubmed: 29425488
Nat Rev Genet. 2019 Aug;20(8):437-455
pubmed: 31086298
Cell. 2017 Mar 23;169(1):13-23
pubmed: 28340338
Cell Rep. 2016 Apr 19;15(3):519-530
pubmed: 27068464
Nat Commun. 2014 Oct 24;5:5207
pubmed: 25342513
Nat Struct Mol Biol. 2018 Sep;25(9):833-840
pubmed: 30127355