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Histone modifications in transcriptional regulation


Histone modifications in transcriptional regulation Shelley L Berger
Covalent modifications of the amino termini of the core histones in nucleosomes have important roles in gene regulation. Research in the past two years reveals these modifications to consist of phosphorylation, methylation and ubiquitination, in addition to the better-characterized acetylation. This multiplicity of modifications, and their occurrence in patterns and dependent sequences, argues persuasively for the existence of a histone code.
Addresses The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA; e-mail: berger@wistar.upenn.edu Current Opinion in Genetics & Development 2002, 12:142–148 0959-437X/02/$ — see front matter ? 2002 Elsevier Science Ltd. All rights reserved. Abbreviations APP amyloid-β precursor protein CBP CREB-binding protein HAT histone acetyltransferases HDAC histone deacetylase β IFN-β interferon-β PCAF p300/CBP-associated factor Rb retinoblastoma protein SAGA Spt-Ada-Gcn5-acetylase complex TBP TATA-binding protein

of DNA-binding transcription factors themselves, which causes increased association with HATs for histone acetylation, indicating the existence of modification cascades [6,7]. It is also important to point out that the transcriptional HATs also have an apparent non-transcriptional role in establishing the global genomic balance of acetylation [8–11]. As the outcome of histone modifications has been examined, two non-exclusive models have emerged. One is that histone modifications affect chromatin structure directly. The second model is that modifications present a special surface for interaction with other proteins. Either model can be reconciled with the histone code hypothesis, both may operate simultaneously, and both have great explanatory power regarding the relationship between histone modification and gene control.

Histone acetylation
While the identities of histone methyltransferases (HMTs), HKs and HUs are still being worked out (see below), many HATs are now known. The most consistent functional characteristic of the HATs is that they are transcriptional coactivators (i.e. they do not bind directly to DNA but rather with DNA-binding activators). The fact that HATs are coactivators rather than DNA-binding moieties underscores the need for flexibility, regulation and alternative strategies in regulating chromatin and the basal transcriptional machinery. Many of the HATs are components of large multisubunit complexes, recruited to promoters by interaction with DNA-bound activator proteins [12]. Two well-studied examples are yeast SAGA/human PCAF/Gcn5 and the yeast NuA4/human Tip60 complexes, which both have transcriptional roles [13,14]. Previous observations have indicated that there are several interaction surfaces within the complexes for association with activators. New data indicates that the Tra1/TRRAP protein is most likely the predominant direct target of activators [15,16]. The Tra1 role is logical, as it is the only conserved subunit between the SAGA and NuA4 complexes, which both interact with activators. The subunit composition of the NuA4-related Tip60 complex in humans indicates that it may have an additional direct role in DNA repair/apoptosis [17]. Before their rebirth as histone acetylation ‘delivery’ vehicles, there was a wealth of evidence that many of the proteins later identified in HAT complexes possessed ‘classic’ coactivator activity, that is, they promote TATAbinding protein (TBP) or other general transcription factor association with the basal promoter [18]. Harking back to these models are new experiments showing that SAGA has non-chromatin-dependent coactivator activity — that is, at some promoters that do not require Gcn5’s acetylation

It is now difficult to recall that a scant five years ago many scientists working in the field of gene regulation believed chromatin was not a central player. Key observations that changed this view were that promoter-associated coactivators and corepressors possessed histone acetylation and deacetylation activity, respectively [1]. Since then, the amount of related research has been staggering, including investigations into identities of histone acetyltransferases (HATs), recognition of other histone modifications, and explorations of mechanisms (e.g. see [2,3] for review). Moreover, understanding HAT/histone deacetylase (HDAC) function has become a useful paradigm for other modifications that are just now being discovered. A unifying concept in this field is that of a histone code, which posits that the totality of modifications, both in kind and number, dictate a particular biological outcome [4,5]. Strongly supporting the histone code hypothesis is evidence for several different covalent modifications, including acetylation, phosphorylation, methylation and ubiquitination (Figure 1a), all involved in gene-specific regulation. In addition, documentation of patterns and order of modification events points to a code (Figure 1b). These ideas culminate in the recognition of ‘off’ and ‘on’ states, characterized by alternative histone modifications. Although beyond the scope of this review, there is an emerging correlation with modifications, such as acetylation,

Histone modifications in transcriptional regulation Berger


Figure 1 Types and patterns of histone covalent modifications and interacting domains. (a) Types of modifications: these include acetylation at Lys (K), phosphorylation at Ser (S), methylation at Arg and Lys (R and K) and ubiquitylation at Lys (K). The two classes of domains that interact with specific modified residues are bromodomain (BrD), which interact with acetlyated lysine and chromodomain (ChrD), which interacts with methylated lysine. (b) Patterns of modifications. Pairs of modifications, and the sequence of the alterations, correlate with either active or repressed transcription. (a) Lysine acetylation K Ac BrD Lysine methylation K Me ChrD Arginine methylation R Me Serine phosphorylation S P Lysine ubiquitylation K Ub


Histone H3 S10 K14 ON P Ac

Histone H4 R3 K8






Current Opinion in Genetics & Development

activity, other components of the SAGA complex are required for full transcription by way of TBP recruitment [19??,20??]. Thus, the complexes are modular, wherein chromatin modification and TBP recruitment are distinct, non-overlapping and independent functions [21]. It is evident that histone modification and ATP-dependent chromatin remodeling are functionally connected for gene regulation as their activities are required at the same promoters in Saccharomyces cerevisiae. However, an important issue is whether there is an actual mechanistic interrelationship between them. One indication of this is that the same activators interact with both SAGA and the ATPdependent Swi/Snf family of chromatin remodeling enzyme complexes [22], providing coordinated promoter recruitment. Recent investigations have also examined the relative timing of recruitment of each class of enzymes. A priori, it is not predictable whether alteration of chromatin structure would precede or follow chemical modification of histone tails, and interestingly, both paradigms seem to operate. In S. cerevisiae, for genes that are transcribed during mitosis when the genome is highly condensed, it appears that Swi/Snf-dependent remodeling occurs before Gcn5-dependent histone acetylation, and is required for acetylation to occur [22,23,24??], suggesting that the HAT complexes cannot penetrate closed chromatin without initial remodeling (Figure 2a). However, for other, highly inducible cell cycle independent genes, histone acetylation appears to occur in advance of ATP-dependent

remodeling (Figure 2b). These include the IFN-β and hormone receptor dependent genes in mammals [25?,26?], and the PHO8 gene in S. cerevisiae [27?]. In vitro, acetylated templates provide more stable Swi/Snf complex binding [28?]. The order of events has been particularly wellcharacterized at the IFN-β promoter: binding of activators to the promoter initiates recruitment of the Gcn5 complex and histone acetylation, which stimulates CREB-binding protein (CBP)/RNA polymerase recruitment, followed by CBP-dependent recruitment of Swi/Snf complex, leading to ATP-dependent sliding of a nucleosome near the TATA box, culminating in TBP binding [25?]. Finally, it is interesting that in vitro, VDJ recombination is stimulated in a concerted fashion by acetylation and Swi/Snf remodeling [29], and thus these activities most likely act together during genomic processes other than transcription. Exemplifying the maturing study of HATs are reports on regulation of HAT activity. A novel broad-spectrum HAT–inhibitor protein complex was isolated from human cells [30]. Two related studies show an unexpected role of DNA-binding factors in modulating the HAT activity of CBP and PCAF, in addition to simple recruitment [31,32]. Although the identity and mechanism of action has dominated the field of chromatin modification in the past five years, the next stage of discovery will be the biological role of these enzymes in higher eukaryotes, including connection to disease. Mouse nulls have been constructed for


Chromosomes and expression mechanisms

Figure 2 Sequence of chromatin changes during transcriptional activation of genes co-dependent upon SAGA and Swi/Snf. (a) During mitosis, ATP-dependent remodeling precedes acetylation. (b) For inducible, cell-cycle-independent genes, acetylation precedes remodeling. Ac, acetylation; TATA, TBP binding sequence; UAS, upstream activating sequence.


Mitotic genes (condensed chromatin)


Inducible genes (poised chromatin)


Closed chromatin Swi/Snf

Open chromatin SAGA Ac Ac



Generalized chromatin opening SAGA/Swi/Snf Ac Ac

Acetylation directed to promoter Swi/Snf Ac




Specific acetylation/alteration at promoter

Alteration directed to promoter
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the homologous HATs, Gcn5 and PCAF. Whereas the PCAF null is normal, Gcn5 has an essential role in early embryonic development that is different from that of the p300 HAT, suggesting separate functions [33?,34]. An interesting connection was made between the Alzheimer’s protein APP and the Tip60 MYST family HAT, in that a cleaved portion of APP and the HAT form a complex to activate as yet unknown target genes [35??]. A second neurodegenerative disease in humans, manifest in the Drosophila melanogaster model system, is caused by polyglutamine repeat expansion in certain proteins such the Huntington’s disease-related abnormal protein Htt. These polyglutamine repeats inhibit HAT activity to manifest the mutant phenotype, which can be ameliorated with HDAC inhibitor treatment [36??]. It is certain that in the near future a great many human diseases will be linked to HATs and other histone modifications.

in mammalian cells, such as the c-Fos gene [38]. The Rsk/Msk families of kinases may cause the phosphorylation directly [39,40]. A transcriptionally-linked histone kinase has been identified in S. cerevisiae as the previously known Snf1 kinase [41??]. The identity of these HKs as previously known transcription-associated factors suggests that they may be recruited to specific promoters as coactivators, much like the HATs and Swi/Snf complexes discussed above. Finally, heat-shock gene induction in Drosophila is accompanied by dramatic increases in histone H3 Ser-10 phosphorylation [42?].

Histone methylation
There are two types of histone methylation, targeting either arginine or lysine residues. Histone arginine methylation is involved in gene activation and, again, methylases are recruited to promoters as coactivators. These are the CARM1/PRMT1 family of HMTs, and they predominantly target either H3 or H4, respectively [43,44?]. The role of the SET domain family of lysine HMTs in heterochromatic gene silencing is very exciting. The heterochromatic Suvar3-9 enzyme in mammalian cells was the first to be shown to have this activity in vitro, to methylate Lys-9 of histone H3 [45?], and the modification targets a well-known silencing protein, called HP1, to heterochromatin [46,47,48?]. Two additional advances are conceptual leaps forward. First, the Suvar39 mechanism is used for gene-specific repression, where it is recruited by corepressors, such as by the tumor suppressor and corepressor Rb (retinoblastoma protein; see Kouzarides, this issue

Histone phosphorylation
Histone phosphorylation involving Ser-10 of histone H3 has also emerged as an important modification, both in transcriptional activation and in chromosome condensation during mitosis [37]. As chromosome condensation and transcription are expected to involve opposing physical alterations of chromatin (i.e. closing of chromatin during mitosis and opening during transcription), the finding that the same modification is involved in both processes is circumstantial support for the modifications-as-binding surfaces rather than direct alteration of chromatin (see below). Initial studies showed that histone phosphorylation has a role in transcriptional induction of immediate early genes

Histone modifications in transcriptional regulation Berger


[pp 198–209]), much like HDAC recruitment to specific genes [49??,50]. Second, it appears that Lys-9 methylation is opposed by a second SET domain lysine methylation at Lys-4 of histone H3, and these alternative modifications beautifully mark areas of gene repression and activation ([51??,52??]; see Grewal and Elgin, this issue [pp 178–187]).

Histone ubiquitination
Two recent developments indicate that histone ubiquitylation is joining the ranks of important modifications. First, in S. cerevisiae, Lys-123 within the H2B carboxy-terminal tail is a substrate for the Rad6 ubiquitin ligase [53]. This modification is critical to mitotic and meiotic growth, although it is not yet clear whether it is involved in transcription. Second, TafII250 in the TBP-associated complex TFIID has been shown to possess histone H1 ubiquitylation activity [54], adding to its long list of enzymatic activities (kinase and HAT activities), which may be involved in transcription.

Patterns, codes and models
Thus, specific modifications correlate with specific transcriptional states. In particular, histone H3 appears to be critical: known marks occur at Lys-4 (methylation), Lys-9 (methylation), Ser-10 (phosphorylation), Lys-14 (acetylation) and Arg-17 (methylation). In fact, around K9/S10/K14 in histone H3 there appear to be specific patterns for inactivity and activity (Figure 1b). An inactive state is characterized by histone deacetylation at Lys-14, which precedes methylation at Lys-9. The enzymes that carry out these modifications are genetically linked in Schizosaccharomyces pombe, and deacetylation at Lys-14 precedes methylation at Lys-9 [51??]. In contrast, acetylation at Lys-14 is preceded by, and dependent upon, phosphorylation at Ser-10. This has been shown in vitro for the Gcn5 acetyltransferase [55,56], and in vivo the Snf1 histone kinase and Gcn5 are a linked pair of enzymes that operate in this sequence [56]. In addition, another transcriptional ‘on’ state within histone H4 consists of methylation at Arg-3 preceding and promoting p300-mediated acetylation at Lys-8 and Lys-12 [44?]. Thus, specific and interlinked modifications may dictate specific genomic states, such as gene activation, repression, DNA repair, recombination, chromosome segregation, and so on. The function of the histone code may be to cause specific changes in activity at the affected loci. These changes could be direct physical alteration of the chromatin, either on a single nucleosome scale to alter histone–DNA contacts, or within a higher order of structure. There is recent genetic evidence for direct electrostatic effects of modifications in Tetrahymena, where the essential function provided by acetylation of amino-terminal tails of the variant H2A histone (H2A.Z) is caused by direct charge alterations, rather than the presence of the actual modification [57?]. Other evidence for direct changes are that the amino-terminal tails appear to be the main regulators of transcription factor access to DNA [58], and that acetylation itself alters the accessibility of DNA for protein binding [59?].

A second possibility is that the modifications create altered surfaces on nucleosomes for interaction with effector proteins that are the actual agents of altered activity. Evidence supporting this model is that certain modifications generate stronger interactions in vitro with domains of chromatin-associated proteins and correlate in vivo with recruitment of these proteins (Figure 1a). Examples include the bromodomain, present in HATs, which has been shown to specifically interact with acetylated lysine. The interaction of Gcn5 with Lys-14 [60?] likely leads to reinforcement of acetylation during gene activation, and the interaction of the double bromodomain of Taf250 with dual acetylated histone H3 or H4 [61] may assist the binding of TFIID to nucleosomes around the TATA box. In S. cerevisiae, substitutions in the bromodomains associated with TFIID show synthetic phenotypes with mutations in acetylatable lysines in histone H4 (S Buratowski, personal communication) arguing for a functional link. A second example is the chromodomain, present in numerous HMTs and other proteins, which in some cases binds to the Lys-9-methylated histone H3 tail. Suvar3-9 methylates Lys-9 during gene silencing, and this leads to increased association of the chromodomain-containing protein HP1, long known to be important in heterochromatic silencing. These data predict the existence of other domains for interaction with the other known, and as yet uncharacterized, histone modifications. For example, the SANT and PHD fingers are additional chromatin-associated domains whose ‘partner’ modifications are not yet identified.

The initial finding that histone acetylation is a regulatory step involved in gene activation has now expanded in many ways. First, histone phosphorylation, methylation and ubiquitylation have each been correlated with gene activation or repression. Future revelations will identify new modifications of specific residues in the tails of histones H3 and H4, and will likely indicate modifications in both the amino and extended carboxy-terminal tails of H2A and H2B. Second, there is an interconnection and interdependence of modifications in the H3 and H4 tails, suggesting specific modification ‘states’ characteristic of transcriptional activation or repression. Intriguing questions are whether dependent sequences will extend beyond two modifications, and whether modification on the tails of different histones — which may be adjacent in chromatin — may influence one another. In general, the number and patterns of modifications, and their apparent correlation with specific states of transcription support the existence of an epigenetic code on the histone terminal tails. Third, specific modifications, such as acetylation and methylation, promote the binding of specialized chromatin domains, such as the bromodomain or chromodomain. To date, it is not clear how general these observations will be: for example, does lysine acetylation invariably lead to bromodomain interaction, and does each modification have a partner chromatin domain? Finally, it is important to emphasize that the alternative mechanistic models for the function of histone modifications


Chromosomes and expression mechanisms

described above — either direct conformational or interaction-surfaces — are useful for experimental design but could well both be biologically relevant. Like all good models, they are intended to stimulate thought and experimental work but reality may incorporate and transcend them both.


Ikura T, Ogryzko VV, Grigoriev M, Groisman R, Wang J, Horikoshi M, Scully R, Qin J, Nakatani Y: Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis. Cell 2000, 102:463-473.

18. Guarente L: Transcriptional coactivators in yeast and beyond. Trends Biochem Sci 1995, 20:517-521. 19. Larschan E, Winston F: The S. cerevisiae SAGA complex functions ?? in vivo as a coactivator for transcriptional activation by Gal4. Genes Dev 2001, 15:1946-1956. See annotation [20??]. 20. Bhaumik SR, Green MR: SAGA is an essential in vivo target of the ?? yeast acidic activator Gal4p. Genes Dev 2001, 15:1935-1945. SAGA contains Gcn5 as a HAT, and this activity is required for many of the promoters that SAGA regulates. However, these two papers show that SAGA regulates some promoters in a Gcn5-independent, but activator-dependent fashion, to recruit TBP and assemble the general transcription machinery. 21. Sterner DE, Grant PA, Roberts SM, Duggan LJ, Belotserkovskaya R, Pacella LA, Winston F, Workman JL, Berger SL: Functional organization of the yeast SAGA complex: distinct components involved in structural integrity, nucleosome acetylation, and TATA-binding protein interaction. Mol Cell Biol 1999, 19:86-98. 22. Peterson CL, Workman JL: Promoter targeting and chromatin remodeling by the SWI/SNF complex. Curr Opin Genet Dev 2000, 10:187-192. 23. Cosma MP, Tanaka T, Nasmyth K: Ordered recruitment of transcription and chromatin remodeling factors to a cell cycle and developmentally regulated promoter. Cell 1999, 97:299-311. 24. Krebs JE, Fry CJ, Samuels ML, Peterson CL: Global role for ?? chromatin remodeling enzymes in mitotic gene expression. Cell 2000, 102:587-598. This paper is a companion to the previous one [23], and extends the observations to show that genes transcribed during mitosis (or set up during mitosis, as HO) are exquisitely dependent upon Swi/Snf and SAGA. Like HO, these genes require Swi/Snf action first, suggesting that the relatively compact chromatin during mitosis requires ATP-dependent remodeling prior to histone modification. 25. Agalioti T, Lomvardas S, Parekh B, Yie J, Maniatis T, Thanos D: ? Ordered recruitment of chromatin modifying and general transcription factors to the IFN-beta promoter. Cell 2000, 103:667-678. This paper and the three following [26?–28?] each argue, using different approaches, that acetylation both precedes and promotes Swi/Snf action. This study continues an exhaustive analysis of transcriptional regulation of the IFN-β promoter, in response to viral infection. Here the authors show that Gcn5 and CBP/RNA polymerase arrive at the promoter first, followed by BRG (an ATP-dependent remodeling enzyme complex), which alters the chromatin for eventual general factor binding. 26. Dilworth FJ, Fromental-Ramain C, Yamamoto K, Chambon P: ? ATP Driven chromatin remodeling activity and histone acetyltransferases act sequentially during transactivation by RAR/RXR in vitro. Mol Cell 2000, 6:1049-1058. This paper extends to nuclear hormone receptors the sequential action of histone acetylation followed by ATP-dependent remodeling. See also annotation [25?]. 27. ? Reinke H, Gregory PD, H?rz W: A transient histone hyperacetylation signal marks nucleosomes for remodeling at the PHO8 promoter in vivo. Mol Cell 2001, 7:529-538. This paper makes the important, and possibly general, point that acetylation occurs rapidly and transiently following induction. Acetylation is ‘frozen’ at the PHO8 promoter in S. cerevisiae by mutating a component of the Swi/Snf complex, thereby eliminating remodeling. The results argue that acetylation occurs before remodeling, and that remodeling removes the mark. See also annotation [25?].

Thanks to Gordon Moore for critical reading of the manuscript. Grant support for research in the lab comes from The National Science Foundation (MCB78940) and The National Institutes of Health (GM55360 and CA78831).

References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:

? of special interest ?? of outstanding interest
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10. Kuo MH, vom Baur E, Struhl K, Allis CD: Gcn4 activator targets Gcn5 histone acetyltransferase to specific promoters independently of transcription. Mol Cell 2000, 6:1309-1320. 11. Howe L, Auston D, Grant P, John S, Cook RG, Workman JL, Pillus L: Histone H3 specific acetyltransferases are essential for cell cycle progression. Genes Dev 2001, 15:3144-3154. 12. Utley RT, Ikeda K, Grant PA, Cote J, Steger DJ, Eberharter A, John S, Workman JL: Transcriptional activators direct histone acetyltransferase complexes to nucleosomes. Nature 1998, 394:498-502. 13. Grant PA, Duggan L, Cote J, Roberts SM, Brownell JE, Candau R, Ohba R, Owen-Hughes T, Allis CD, Winston F et al.: Yeast Gcn5 functions in two multisubunit complexes to acetylate nucleosomal histones: characterization of an Ada complex and the SAGA (Spt/Ada) complex. Genes Dev 1997, 11:1640-1650. 14. Galarneau L, Nourani A, Boudreault AA, Zhang Y, Heliot L, Allard S, Savard J, Lane WS, Stillman DJ, Cote J: Multiple links between the NuA4 histone acetyltransferase complex and epigenetic control of transcription. Mol Cell 2000, 5:927-937. 15. Brown CE, Howe L, Sousa K, Alley SC, Carrozza MJ, Tan S, Workman JL: Recruitment of HAT complexes by direct activator interactions with the ATM-related Tra1 subunit. Science 2001, 292:2333-2337. 16. Park J, Kunjibettu S, McMahon SB, Cole MD: The ATM-related domain of TRRAP is required for histone acetyltransferase recruitment and Myc-dependent oncogenesis. Genes Dev 2001, 15:1619-1624.

28. Hassan AH, Neely KE, Workman JL: Histone acetyltransferase ? complexes stabilize Swi/Snf binding to promoter nucleosomes. Cell 2001, 104:817-827. The stability of Swi/Snf interaction with an immobilized chromatinized template is increased if nucleosomes are pre-acetylated. This suggests that the Swi/Snf complex detects the acetylation and uses it as a surface for interaction. See also annotation [25?]. 29. Kwon J, Morshead KB, Guyon JR, Kingston RE, Oettinger MA: Histone acetylation and hSWI/SNF remodeling act in concert to stimulate V(D)J cleavage of nucleosomal DNA. Mol Cell 2000, 6:1037-1048.

Histone modifications in transcriptional regulation Berger


30. Seo SB, McNamara P, Heo S, Turner A, Lane WS, Chakravarti D: Regulation of histone acetylation and transcription by INHAT, a human cellular complex containing the set oncoprotein. Cell 2001, 104:119-130. 31. Chen CJ, Deng Z, Kim AY, Blobel GA, Lieberman PM: Stimulation of CREB binding protein nucleosomal histone acetyltransferase activity by a class of transcriptional activators. Mol Cell Biol 2001, 21:476-487. 32. Soutoglou E, Viollet B, Vaxillaire M, Yaniv M, Pontoglio M, Talianidis I: Transcription factor-dependent regulation of CBP and P/CAF histone acetyltransferase activity. EMBO J 2001, 20:1984-1992. 33. Xu W, Edmondson DG, Evrard YA, Wakamiya M, Behringer RR, ? Roth SY: Loss of Gcn5l2 leads to increased apoptosis and mesodermal defects during mouse development. Nat Genet 2000, 26:229-232. Two mouse null lines of homologues of yeast Gcn5 have been created: one deleted for PCAF and the second for Gcn5. The results indicate that Gcn5 is critical for mesoderm lineages in early development and loss causes embryonic lethality, whereas PCAF loss has no apparent phenotype. In addition, the phenotype of the Gcn5 null is distinct from that of p300, which is a physically interacting HAT. Thus acetyltransferases have distinct functional roles in mammals. 34. Yamauchi T, Yamauchi J, Kuwata T, Tamura T, Yamashita T, Bae N, Westphal H, Ozato K, Nakatani Y: Distinct but overlapping roles of histone acetylase PCAF and of the closely related PCAF-B/GCN5 in mouse embryogenesis. Proc Natl Acad Sci USA 2000, 97:11303-11306. 35. Cao X, Sudhof TC: A transcriptionally active complex of APP with ?? Fe65 and histone acetyltransferase Tip60. Science 2001, 293:115-120. The APP protein, associated with Alzeimer’s disease, is normally membraneassociated and cleaved into extracellular — the region that accumulates into plaques — and intracellular domains. The intracellular (nuclear) domain associates into a complex with Tip60 and activates transcription, suggesting that one role of APP is to alter the chromatin of target genes. 36. Steffan JS, Bodai L, Pallos J, Poelman M, McCampbell A, Apostol BL, ?? Kazantsev A, Schmidt E, Zhu YZ, Greenwald M et al.: Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 2001, 413:739-743. There are several proteins that possess repeats of glutamine, and expansion of these polyglutamine repeats is a cause of neurodegeneration in humans and in the model D. melanogaster. Here it is shown that expanded polyglutamine repeats bind to both PCAF and CBP HATs and inhibit their enzymatic activity. Application of HDAC inhibitors reverses neurodegeneration in the Drosophila eye caused by the repeat expansion, suggesting that this mechanism has a causative role in the mutant state. 37. Cheung P, Allis CD, Sassone-Corsi P: Signaling to chromatin through histone modifications. Cell 2000, 103:263-271.

physiological response. Immunofluorescence shows that the level of histone H3 Ser-10 phosphorylation increases dramatically at the heat-shock loci, where acetylation of histones is not visibly altered, suggesting that histone phosphorylation is the critical modification for the transcriptional response. 43. Chen D, Ma H, Hong H, Koh SS, Huang SM, Schurter BT, Aswad DW, Stallcup MR: Regulation of transcription by a protein methyltransferase. Science 1999, 284:2174-2177. 44. Wang H, Huang ZQ, Xia L, Feng Q, Erdjument-Bromage H, Strahl BD, ? Briggs SD, Allis CD, Wong J, Tempst P, Zhang Y: Methylation of histone H4 at arginine 3 facilitating transcriptional activation by nuclear hormone receptor. Science 2001, 293:853-857. Previous observations indicate that the CARM1/PRMT1 family of protein arginine methyltransferases are transcriptional coactivators and methylate histones in vitro. In this study, histones are shown to be methylated in vivo, suggesting that arginine methylation of histones is physiologically relevant. It is shown that acetylation of Lys-8 in histone H4 in vitro promotes methylation of Arg-3. The linkage of these modifications is another example of comodification during gene activation, supporting the histone code hypothesis. 45. Rea S, Eisenhaber F, O’Carroll D, Strahl BD, Sun ZW, Schmid M, ? Opravil S, Mechtler K, Ponting CP, Allis CD, Jenuwein T: Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 2000, 406:593-599. This was the first report of histone lysine methylation in vitro by a specific enzyme, Suvar3-9, which was previously correlated with heterochromatic silencing. This finding opened up the idea that lysine methylation is regulatory, a notion that is of current intense interest. 46. Nakayama J, Rice JC, Strahl BD, Allis CD, Grewal SI: Role of histone ? H3 lysine 9 methylation in epigenetic control of heterochromatin assembly. Science 2001, 292:110-1113. Previous observations indicated that members of the SET domain family of proteins are histone lysine methyltransferases targeting Lys-9 of histone H3. This report extends these observations to show that Lys-9 is methylated at in the heterochromatic region of the mating type locus in S. pombe, and mutation of Clr4, the SET homologue of the Suvar3-9 histone methyltransferase, eliminated the methylation and correlatively lowered gene silencing. This is the first clear genetic demonstration of Lys-9 methylation and its importance in vivo. Bannister AJ, Zegerman P, Partridge JF, Miska EA, Thomas JO, Allshire RC, Kouzarides T: Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 2001, 410:120-124. This paper and the following report [48?] show that Lys-9 methylation in histone H3 creates a stronger binding surface for the heterochromatic protein HP1. The authors demonstrate both direct interaction of the chromodomain in HP1 with methylated Lys-9, and Lys-9-methylation-dependent binding of HP1 to the mating type locus in S. pombe. Thus, this is the second example, in addition to acetylated lysine-dependent binding of the bromodomain, of a specific interaction between a chromatin-associated domain and a modified histone residue. 48. Lachner M, O’Carroll D, Rea S, Mechtler K, Jenuwein T: Methylation ? of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 2001, 410:116-120. This paper, like the previous one [47?], shows that the chromodomain of HP1 binds better to methylated Lys-9 relative to the unmodified tail. 49. Nielsen SJ, Schneider R, Bauer UM, Bannister AJ, Morrison A, ?? O’Carroll D, Firestein R, Cleary M, Jenuwein T, Herrera RE, Kouzarides T: Rb targets histone H3 methylation and HP1 to promoters. Nature 2001, 412:561-565. This paper extends the role of histone H3 Lys-9 methylation to gene-specific repression. The authors demonstrate that the tumor suppressor and corepressor Rb associates with the promoter to target methylation of Lys-9 of histone H3, and HP1, to the promoter. This suggests that gene specific repression mechanisms may generally involve not only histone deacetylation, but also histone methylation. 50. Vandel L, Nicolas E, Vaute O, Ferreira R, Ait-Si-Ali S, Trouche D: Transcriptional repression by the retinoblastoma protein through the recruitment of a histone methyltransferase. Mol Cell Biol 2001, 21:6484-6494. 51. Noma K, Allis CD, Grewal SI: Transitions in distinct histone H3 ?? methylation patterns at the heterochromatin domain boundaries. Science 2001, 293:1150-1155. This paper, and the following [52??] are the first to show that histone H3 K9methylation and K4-methylation oppose one another to create gene-silencing heterochromatic chromatin versus gene-activating chromatin. They study the mating type locus in S. pombe and demonstrate that a boundary between K9-me/K-me exists at the boundary between heterochromatin and open chromatin, and altering this boundary by mutation alters the boundary of K9-me/K4-me accordingly. The opposition of these marks supports the histone code hypothesis. 47. ?

38. 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. 39. 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. 40. Thomson S, Clayton AL, Hazzalin CA, Rose S, Barratt MJ, Mahadevan LC: The nucleosomal response associated with immediate-early gene induction is mediated via alternative MAP kinase cascades: MSK1 as a potential histone H3/HMG-14 kinase. EMBO J 1999, 18:4779-4793. 41. Lo WS, Duggan L, Tolga NC, Emre, Belotserkovskya R, Lane WS, ?? Shiekhattar R, Berger SL: Snf1 — a histone kinase that works in concert with the histone acetyltransferase Gcn5 to regulate transcription. Science 2001, 293:1142-1146. Previous observations indicated that acetylation at Lys-14 in histone H3 is stimulated by prior phosphorylation at Ser-10. In this study, a Ser-10 kinase is identified in S. cerevisiae as the transcription factor Snf1 kinase. Snf1 and Gcn5 are shown to coregulate transcription of the INO1 gene, by sequential and linked phosphorylation and acetylation. The existence of a particular pattern of modifications supports the histone code hypothesis. 42. Nowak SJ, Corces VG: Phosphorylation of histone H3 correlates ? with transcriptionally active loci. Genes Dev 2000, 14:3003-3013. During the heat-shock response in D. melanogaster, the genome is reprogrammed to shut down transcription of most genes and initiate high level transcription of a few genes whose products are required for the


Chromosomes and expression mechanisms

52. Litt MD, Simpson M, Gaszner M, Allis CD, Felsenfeld G: Correlation ?? between histone lysine methylation and developmental changes at the chicken beta-globin locus. Science 2001, 293:2453-2455. This paper shows that modification of histone H3 becomes altered at the chicken β-globin locus during mouse development. Developmental changes in the large-scale pattern across the locus of K4-methylation mimics the pattern of K14-acetylation, and thus marks an ‘active’ code. In contrast, the K9methylation pattern is in direct opposition across the locus and correlates with condensed chromatin, thus representing an ‘inactive’ code. See also annotation [51??]. 53. Robzyk K, Recht J, Osley MA: Rad6-dependent ubiquitination of histone H2B in yeast. Science 2000, 287:501-504. 54. Pham AD, Sauer F: Ubiquitin-activating/conjugating activity of TAFII250, a mediator of activation of gene expression in Drosophila. Science 2000, 289:2357-2360. 55. Cheung P, Tanner KG, Cheung WL, Sassone-Corsi P, Denu JM, Allis CD: Synergistic coupling of histone H3 phosphorylation and acetylation in response to epidermal growth factor stimulation. Mol Cell 2000, 5:905-915. 56. 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.

57. Ren Q, Gorovsky MA: Histone H2A.Z acetylation modulates an ? essential charge patch. Mol Cell 2001, 7:1329-1335. This report shows that charge alteration caused by histone acetylation is itself responsible for the essential acetylation phenotype in the H2A.Z amino terminal tail. The authors alter the lysines that are acetylated in histone H2A.Z to mimic the charge manifested by acetylation, and observe the identical phenotype as caused by acetylation itself. 58. Vitolo JM, Thiriet C, Hayes JJ: The H3-H4 N-terminal tail domains are the primary mediators of transcription factor IIIA access to 5S DNA within a nucleosome. Mol Cell Biol 2000, 20:2167-2175. 59. Anderson JD, Lowary PT, Widom J: Effects of histone acetylation on ? the equilibrium accessibility of nucleosomal DNA target sites. J Mol Biol 2001, 307:977-985. This report shows that histone acetylation alone causes increased association of proteins with their target sites in nucleosomal DNA. This indicates that the charge alteration caused by acetylation is sufficient to allow binding of proteins, supporting the hypothesis that the charge alteration by acetylation, is per se responsible for chromatin alteration. 60. 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. 61. Jacobson RH, Ladurner AG, King DS, Tjian R: Structure and function of a human TAFII250 double bromodomain module. Science 2000, 288:1422-1425.


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