the genetics and biochemistry of chromatin remodeling complexes: large, multisubunit
catalytic entities perform the work of histone modification that leads either to transcriptionalactivation or repression of target genes. Here, promoter selectivity for sequence-specificDNA binding proteins must guide the assembly of these big chromatin-modifying machines,yet the genetic regulatory elements must also be able to respond rapidly to changingtranscriptional requirements. Active investigation of chromatin remodeling continues inmany laboratories, from the level of sequence-specific modification of specific histones tothe level of multiprotein complex assembly.
A particular protein motif called a “bromodomain” has been noticed in many of the proteinsthat compose the chromatin modifying machinery. It was first identified in 1992 as a 61 – 63amino acid signature (14). Although it lacked a known function at the time, it has
subsequently been identified in transcription factors, co-activators and other proteins that areimportant in transcription or chromatin remodeling and its boundaries have been expandedto about 110 amino acids. The number of such proteins was about forty at last report (15,16)and several important additions to the family have been made since then. The first describedbromodomain protein, yeast Gcn5 (17), was shown to be necessary for amino acid
metabolism and was characterized as a transcriptional co-activator (18). It provides a histoneacetylation (19) component of the ADA (Adapter) and SAGA (Spt-Ada-Gcn5
acetyltransferase) transcription complexes (20), which is fundamental and essential forviability (21). Gcn5 is also structurally related to the mammalian proteins CBP, p300 andHat1 (22). In mammals, CBP and p300 also have intrinsic HAT activity (23,24) and interactwith many important transcription factors as co-activators of transcription. Virtually all ofthe nuclear histone acetyltransferases (HATs) contain bromodomains (16), but not allbromodomain proteins are HATs. For example, other classes of bromodomain proteinsinclude MLL, a putative transcription factor (25,26) that interacts with the SWI/SNF
chromatin remodeling complex (27); Spt7, an acidic transcriptional activator and componentof the SAGA complex (28); and a helicase superfamily that includes Snf2, Rsc1/Rsc2 andSth1, components of the SWI/SNF (29) and RSC complexes (30); Brg1, which binds RB(31,32); and brahma, which also contacts RB, is related to Swi2/Snf2 (33,34) and hashomeotic functions in Drosophila (35–37). The role of bromodomains in transcription
complexes has been controversial because their deletion has widely different consequences:in yeast, bromodomain deletion of Spt7 has no phenotype, of Snf2 causes slow growth, butdeletion of Sth1, Rsc1 and Rsc2 causes lethality (16). Much of the apparent significance ofbromodomain proteins lies in their either having intrinsic HAT activity, or being associatedwith promoter-bound complexes that contain HAT or histone deacetylase (HDAC) activity.Bromodomain proteins are thereby potentially important players in the transcriptionalcontrol of a wide variety of eukaryotic genes, including those that control growth.
The bromodomain proteins that interact with RB highlight an important duality in
transcriptional control: the need also to turn promoters off. In particular, the transcriptionalcontrol of E2F-regulated mammalian cell cycle genes is essential for proper progressionthrough each stage of the cell cycle. Whereas transcriptional activation of one set of genes isnecessary to enter a stage of the cell cycle, repression of certain other genes associated withthe previous stage is necessary to exit from that stage. RB (and its family members p107 andp130) bind to E2F proteins and block their transcription activation function (38,39).Recent evidence has revealed that in addition to this direct repression, RB also recruits ahistone deacetylase (40,41), as do p107 and p130 (42), through cooperation with mammalianbrahma and other proteins in the SWI/SNF complex (31,32). Coordinated transcriptionalactivation and repression of the key E2F-regulated mammalian cell cycle genes cyclin E,cyclin A and cdc2 permit proper transitions between G1 and S phases, and S and G2 phases(43). This dual nature of chromatin remodeling complexes was first suspected in yeast,
Front Biosci. Author manuscript; available in PMC 2011 February 7.
DenisNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptPage 3
where SWI/SNF complexes, initially associated with transcriptional activation (44), werelater linked to repression as well: more genes are activated than repressed by SWI/SNFmutations (45). It now appears that SWI/SNF function may establish a widely applicableparadigm in chromatin remodeling complexes, whereby transcriptionally active euchromatincan be converted to inactive heterochromatin and vice versa in part through the exchange ofHAT and HDAC enzymes in the complex (46). This model has been refined lately with theobservation in yeast that several inducible genes active during interphase can recruit HATactivity independently of SWI/SNF, whereas mitotic genes require SWI/SNF to recruit HATactivity (47). This observation emphasizes the importance of coordinated complex formationfor proper transit of the cell cycle.
A central development in the field of bromodomain-containing proteins came with a reportof Zhou and colleagues (48), who used nuclear Overhauser enhancements to solve thesolution structure of the bromodomain of p/CAF in association with N-acetylated lysine.The highly conserved structure of bromodomain proteins suggests a hypothesis that many ofthem will bind N-acetyl-lysine in histones, however by no means will this necessarily betrue for all. The presence of bromodomains in many proteins that are known independentlyto possess HAT activity strongly supports the Zhou hypothesis. A looser notion that thismotif is present in proteins that are involved in chromatin modification and transcriptionregulation is the best guide to their classification at the moment. The future discovery ofbromodomains in proteins that are uninvolved in chromatin restructuring will be a test of theutility of such a classification.
In this special issue, several authors have been invited to contribute their perspectives on thedeveloping field of bromodomain proteins and associated chromatin-modifying activities.Major questions that they address continue to provoke the development of the field, andinclude:
A.What are the number and type of histone modifications, including phosphorylation,
acetylation, methylation, ADP-ribosylation and ubiquitylation, that could regulatethe recruitment of different classes of chromatin-modifying enzymes and mightthese represent a kind of combinatorial “histone code”? How do modifications ofbromodomain-containing proteins reciprocally affect histone modificationactivities?B.Should bromodomain-containing proteins be thought of as a kind of bridge or
platform that recruits diverse enzymatic activities, such as HATs, HDACs, kinasesor helicases, to chromatin? Why are these activities present in some bromodomain-containing proteins as independently-folding domains of a single polypeptide chainand in other cases as separate proteins? Does the weak affinity constant for a singlebromodomain binding to N-acetyl-lysine (~0.1 mM) imply that bromodomains canfunction only in multiprotein complexes with multiple interaction sites?C.Do different bromodomains have different functions, including those that are
present more than once in a single protein? For example, double bromodomains,such as those in TAFII250 might provide mutual cooperativity for protein bindingto chromatin or might interfere with binding instead; or they might conferdifferential promoter specificity.D.Why are some bromodomains essential for enzymatic function or cell viability
whereas deletion of others has no apparent phenotype? Does this behavior reflectredundancy within bromodomain-containing complexes, so that for example SWI/SNF activities on some promoters can partially substitute for HAT-containingcomplexes such as SAGA?
Front Biosci. Author manuscript; available in PMC 2011 February 7.
DenisPage 4
E.What is the significance of the time order of recruitment of SWI/SNF activities and
HAT activities to certain promoters? Why does SWI/SNF recruitment of HATactivity impact yeast transcriptional activation during late mitosis (47), whereasmany inducible promoters recruit HATs independently of SWI/SNF earlier in thecell cycle, and how widespread is this behavior in eukaryotes?
NIH-PA Author ManuscriptAcknowledgments
The author’s work is supported by grant CA75107 from NIH.
References
NIH-PA Author ManuscriptNIH-PA Author Manuscript1. Bradbury EM. Reversible histone modifications and the chromosome cell cycle. Bioessays1992;14:9–16. [PubMed: 1312335]
2. Wolffe AP, Pruss D. Targeting chromatin disruption: Transcription regulators that acetylatehistones. Cell 1996;84:817–819. [PubMed: 8601304]
3. Roth SY, Allis CD. Histone acetylation and chromatin assembly: a single escort, multiple dances?Cell 1996;87:5–8. [PubMed: 8858142]
4. Grunstein M. Histone acetylation in chromatin structure and transcription. Nature 1997;389:349–352. [PubMed: 9311776]
5. Tyler JK, Kadonaga JT. The “dark side” of chromatin remodeling: repressive effects ontranscription. Cell 1999;99:443–446. [PubMed: 10589670]
6. Cheung P, Allis CD, Sassone-Corsi P. Signaling to chromatin through histone modifications. Cell2000;103:263–271. [PubMed: 11057899]
7. Orphanides G, Reinberg D. RNA polymerase II elongation through chromatin. Nature2000;407:471–475. [PubMed: 11028991]
8. Cheung P, Tanner KG, Cheung WL, Sassone-Corsi P, Denu JM, Allis CD. Synergistic coupling ofhistone H3 phosphorylation and acetylation in response to epidermal growth factor stimulation. MolCell 2000;5:905–915. [PubMed: 10911985]
9. Lo WS, Trievel RC, Rojas JR, Duggan L, Hsu JY, Allis CD, Marmorstein R, Berger SL.
Phosphorylation of serine 10 in histone H3 is functionally linked in vitro and in vivo to Gcn5-mediated acetylation at lysine 14. Mol Cell 2000;5:917–926. [PubMed: 10911986]
10. Mahadevan LC, Willis AC, Barratt MJ. Rapid histone H3 phosphorylation in response to growth
factors, phorbol esters, okadaic acid and protein synthesis inhibitors. Cell 1991;65:775–783.[PubMed: 2040014]
11. Sassone-Corsi P, Mizzen CA, Cheung P, Crosio C, Monaco L, Jacquot S, Hanauer A, Allis CD.
Requirement of Rsk-2 for epidermal growth factor-activated phosphorylation of histone H3.Science 1999;285:886–891. [PubMed: 10436156]
12. Chadee DN, Hendzel MJ, Tylipski CP, Allis CD, Bazett-Jones DP, Wright JA, Davie JR. Increased
Ser-10 phosphorylation of histone H3 in mitogen-stimulated and oncogene-transformed mousefibroblasts. J Biol Chem 1999;274:24914–24920. [PubMed: 10455166]
13. Wei Y, Yu L, Bowen J, Gorovsky MA, Allis CD. Phosphorylation of histone H3 is required for
proper chromosome condensation and segregation. Cell 1999;97:99–109. [PubMed: 10199406]14. Haynes SR, Dollard C, Winston F, Beck S, Trowsdale J, Dawid IB. The bromodomain: a
conserved sequence found in human, Drosophila and yeast proteins. Nucl Acids Res1992;20:2603. [PubMed: 1350857]
15. Jeanmougin F, Wurtz JM, Le Douarin B, Chambon P, Losson R. The bromodomain revisited.
Trends Biochem Sci 1997;22:151–153. [PubMed: 9175470]
16. Winston F, Allis CD. The bromodomain: a chromatin-targeting module? Nature Struct Biol
1999;6:601–604. [PubMed: 10404206]
17. Hinnebusch AG, Fink GR. Positive regulation in the general amino acid control of Saccharomyces
cerevisiae. Proc Nat’l Acad Sci USA 1983;80:5374–5378.
18. Guarente L. Transcriptional coactivators in yeast and beyond. Trends Biochem Sci 1995;20:517–
521. [PubMed: 8571454]
Front Biosci. Author manuscript; available in PMC 2011 February 7.
DenisNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptPage 5
19. Struhl K. Histone acetylation and transcriptional regulatory mechanisms. Genes Dev 1998;12:599–
606. [PubMed: 9499396]
20. Wang L, Liu L, Berger SL. Critical residues for histone acetylation by Gcn5, functioning in Ada
and SAGA complexes, are also required for transcriptional function in vivo. Genes Dev1998;12:640–653. [PubMed: 9499400]
21. Kuo MH, Brownell JE, Sobel RE, Ranalli TA, Cook RG, Edmondson DG, Roth SY, Allis CD.
Transcription-linked acetylation by Gcn5p of histone H3 and H4 at specific lysines. Nature1996;383:269–272. [PubMed: 8805705]
22. Dutnall RN, Tafrov ST, Sternglanz R, Ramakrishnan V. Structure of the histone acetyltransferase
Hat1: A paradigm for the GCN5-related N-acetyltransferase superfamily. Cell 1998;94:427–438.[PubMed: 9727486]
23. Bannister AJ, Kouzarides T. The CBP co-activator is a histone acetyltransferase. Nature
1996;384:641–643. [PubMed: 8967953]
24. Ogryzko VV, Schiltz OL, Russanova V, Howard BH, Nakatani Y. The transcriptional co-activators
p300 and CBP are histone acetyltransferases. Cell 1996;87:953–959. [PubMed: 8945521]
25. Gu Y, Nakamura T, Alder H, Prasad R, Canaani O, Cimino G, Croce CM, Canaani E. The t(4;11)
chromosomal translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophilatrithorax, to the AF-4 gene. Cell 1992;71:701–708. [PubMed: 1423625]
26. Tkachuk DC, Kohler S, Cleary ML. Involvement of a homolog of Drosophila trithorax by 11q23
chromosomal translocations in acute leukemias. Cell 1992;71:691–700. [PubMed: 1423624]27. Rozenblatt-Rosen O, Rozovskaia T, Burakov D, Sedkov Y, Tillib S, Blechman J, Nakamura T,
Croce CM, Mazo A, Canaani E. The C-terminal SET domains of ALL-1 and TRITHORAX
interact with the INI1 and SNR1 proteins, components of the SWI/SNF complex. Proc Nat’l AcadSci USA 1998;95:4152–4157.
28. Gansheroff LJ, Dollard C, Tan P, Winston F. The Saccharomyces cerevisiae SPT7 gene encodes a
very acidic protein important for transcription in vivo. Genetics 1995;139:523–536. [PubMed:7713415]
29. Peterson CL, Tamkun JW. The SWI-SNF complex: a chromatin remodeling machine? Trends
Biochem Sci 1995;20:143–146. [PubMed: 7770913]
30. Cairns BR, Lorch Y, Li Y, Zhang M, Lacomis L, Erdjument-Bromage H, Tempst P, Du J, Laurent
B, Kornberg RD. RSC, an essential, abundant chromatin-remodeling complex. Cell1996;87:1249–1260. [PubMed: 8980231]
31. Trouche D, Le Chalony C, Muchardt C, Yaniv M, Kouzarides T. RB and hbrm cooperate to
repress the activation functions of E2F1. Proc Nat’l Acad Sci USA 1997;94:11268–11273.32. Muchardt C, Yaniv M. The mammalian SWI/SNF complex and the control of cell growth. Sem
Cell Dev Biol 1999;10:189–195.
33. Tamkun JW, Deuring R, Scott MP, Kissenger M, Pattatucci AM, Kaufman TC, Kennison JA.
brahma - a regulator of Drosophila homeotic genes structurally related to the yeast transcriptionalactivator SWI2/SNF2. Cell 1992;68:561–572. [PubMed: 1346755]
34. Pazin MJ, Kadonaga JT. SWI2/SNF2 and related proteins: ATP-driven motors that disrupt protein-DNA interactions? Cell 1997;88:737–740. [PubMed: 9118215]
35. Kennison JA, Tamkun JW. Dosage-dependent modifiers of Polycomb and Antennapedia mutations
in Drosophila. Proc Nat’l Acad Sci USA 1988;85:8136–8140.
36. Elfring LK, Deuring R, McCallum CM, Peterson CL, Tamkun JW. Identification and
characterization of Drosophila relatives of the yeast transcriptional activator SNF2/SWI2. MolCell Biol 1994;14:2225–2234. [PubMed: 7908117]
37. Elfring LK, Daniel C, Papoulas O, Deuring R, Sarte M, Moseley S, Beek SJ, Waldrip WR,
Daubresse G, DePace A, Kennison JA, Tamkun JW. Genetic analysis of brahma: the Drosophilahomolog of the yeast chromatin remodeling factor SWI2/SNF2. Genetics 1998;148:251–265.[PubMed: 9475737]
38. Dyson N. The regulation of E2F by pRB-family proteins. Genes Dev 1998;12:2245–2262.
[PubMed: 9694791]
39. Nevins JR. Toward an understanding of the functional complexity of the E2F and retinoblastoma
families. Cell Growth Diff 1998;9:585–593. [PubMed: 9716176]
Front Biosci. Author manuscript; available in PMC 2011 February 7.
DenisNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptPage 6
40. Brehm A, Miska EA, McCance DJ, Reid JL, Bannister AJ, Kouzarides T. Retinoblastoma protein
recruits histone deacetylase to repress transcription. Nature 1998;391:597–601. [PubMed:9468139]
41. Magnaghi-Jaulin L, Groisman R, Naguibneva I, Robin P, Lorain S, Le Villain JP, Troalen F,
Trouche D, Harel-Bellan A. Retinoblastoma protein represses transcription by recruiting a histonedeacetylase. Nature 1998;391:601–605. [PubMed: 9468140]
42. Ferreira R, Magnaghi-Jaulin L, Robin P, Harel-Bellan A, Trouche D. The three members of the
pocket proteins family share the ability to repress E2F activity through recruitment of a histonedeacetylase. Proc Nat’l Acad Sci USA 1998;95:10493–10498.
43. Zhang HS, Gavin M, Dahiya A, Postigo AA, Ma D, Luo RX, Harbour JW, Dean DC. Exit from G1
and S phase of the cell cycle is regulated by repressor complexes containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF. Cell 2000;101:79–89. [PubMed: 10778858]
44. Burns LG, Peterson CL. The yeast SWI-SNF complex facilitates binding of a transcriptional
activator to nucleosomal sites in vivo. Mol Cell Biol 1997;17:4811–4819. [PubMed: 9234737]45. Holstege FC, Jennings EG, Wyrick JJ, Lee TI, Hengartner CJ, Green MR, Golub TR, Lander ES,
Young RA. Dissecting the regulatory circuitry of a eukaryotic genome. Cell 1998;95:717–728.[PubMed: 9845373]
46. Heinzel T, Lavinsky RM, Mullen TM, Soderstrom M, Laherty CD, Torchia J, Yang WM, Brard G,
Ngo SD, Davie JR, Seto E, Eisenman RN, Rose DW, Glass CK, Rosenfield MG. A complexcontaining N-CoR, mSin3 and histone deacetylase mediates transcriptional repression. Nature1997;387:43–48. [PubMed: 9139820]
47. Krebs JE, Fry CJ, Samuels ML, Peterson CL. Global role for chromatin remodeling enzymes in
mitotic gene expression. Cell 2000;102:587–598. [PubMed: 11007477]
48. Dhalluin C, Carlson JE, Zeng L, He C, Aggarwal AK, Zhou MM. Structure and ligand of a histone
acetyltransferase bromodomain. Nature 1999;399:491–496. [PubMed: 10365964]
Front Biosci. Author manuscript; available in PMC 2011 February 7.
因篇幅问题不能全部显示，请点此查看更多更全内容