REVIEW

Chromatin Remodeling and Transcriptional Regulation

Robin X. Luo, Douglas C. Dean

Affiliation of authors: Division of Molecular Oncology, Washington University School of Medicine, St. Louis, MO.

Correspondence to: Douglas C. Dean, Ph.D., Division of Molecular Oncology, Campus Box 8069, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO 63110 (e-mail ddean{at}im.wustl.edu).


    ABSTRACT
 Top
 Abstract
 Chromosome Structure and...
 Histone Acetylation and...
 Histone Deacetylation and...
 Other Chromosome-Remodeling...
 A General Model of...
 Connection Between Chromosome...
 References
 
Extensive studies in the past few years have begun to demonstrate that chromosome structure plays a critical role in transcriptional regulation. Two highly conserved mechanisms for altering chromosome structure have been identified: 1) post-translational modification of histones and 2) adenosine triphosphate (ATP)-dependent chromosome remodeling. Acetylation of histone lysine residues has been known for three decades to be associated with transcriptional activation. Recent discoveries, however, show that a number of transcriptional regulators are histone acetylases or histone deacetylases. Specific DNA-binding transcription factors recruit histone acetylases and deacetylases to promoters to activate or repress transcription. These results strongly support the notion that histone acetylation and deacetylation play an important role in transcriptional regulation. Recent findings have also provided insight into the molecular mechanisms by which ATP-dependent chromosome-remodeling activities participate in transcriptional regulation. Furthermore, some ATP-dependent chromosome-remodeling activities have been shown to complex with histone deacetylases. In the complexes studied to date, the ATP-dependent chromosome-remodeling activity enhances the histone deacetylase activity. Therefore, the two mechanisms appear to work in concert to achieve precise control of transcription. Disruption of chromosome remodeling has been linked to a number of diseases, and a complete understanding of the complex chromosome-remodeling machinery may lead to the development of new therapies.



    CHROMOSOME STRUCTURE AND TRANSCRIPTION
 Top
 Abstract
 Chromosome Structure and...
 Histone Acetylation and...
 Histone Deacetylation and...
 Other Chromosome-Remodeling...
 A General Model of...
 Connection Between Chromosome...
 References
 
DNA in the eukaryotic nucleus is packaged into highly organized chromatin. The basic structural unit of the chromatin is the nucleosome, which consists of approximately 146 base pairs of DNA wrapped around a histone octamer core containing two molecules each of core histones H2A, H2B, H3, and H4. The nucleosome core, with the addition of linker DNA and histone H1, constitutes the fundamental repeating unit of chromatin. Nucleosome arrays are then further assembled into higher order chromatin structures. At least one functional consequence of chromatin packaging is to prevent access of DNA-binding proteins that regulate transcription to the promoter. Biochemical evidence and genetic evidence demonstrate that nucleosomes are normally repressive for transcription [reviewed in (1)]. However, chromosome structure is quite dynamic. It goes through extensive remodeling that leads to either activation or repression of transcription. At least two highly conserved chromosome-remodeling activities have been found in eukaryotic cells: 1) post-translational modification of histones and 2) an adenosine triphosphate (ATP)-dependent chromosome-remodeling activity.

Extensive post-translational modifications, such as acetylation, phosphorylation, and methylation, occur on histone tails [reviewed in (2)] (Fig. 1)Go. The best studied histone modification is the acetylation of core histone tails. Acetylation of histones was first proposed more than 30 years ago to be linked to transcriptional activation in eukaryotic cells (3,4). Subsequently, acetylated histones were shown to preferentially associate with transcriptionally active chromatin (5-7). Acetylation occurs at conserved lysine residues on the amino terminal tails of core histones, such as lysine 8 and lysine 16 on H4, lysine 9 and lysine 14 on H3, and so forth [reviewed in (2)]. It is not totally clear how acetylation makes DNA more accessible to transcription factors. The prevailing thought is that, by the addition of acidic acetyl groups to lysine residues on the histone tails, the basic nature of histones is somewhat neutralized, which decreases their affinity for DNA. As a consequence, nucleosome conformation is altered, which leads to increased accessibility of transcriptional regulators to chromatin templates [reviewed in (8)]. However, the implication from the recent crystallization of the nucleosome core challenges this view.



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Fig. 1. Regulation of nucleosome structure and transcription by acetylation/deacetylation of histones. See text for an in-depth discussion of factors and mechanisms. Ac = acetylated histone tails; BTC = the basal transcription complex; HAT = histone acetyltransferase; HDAC = histone deacetylase. Panels A and C depict conformational alterations in histone and nucleosome structure, respectively, as a result of acetylation. Panels B and D illustrate the transcriptional effects of recruiting HAT and HDAC, respectively.

 
The crystal structure of the nucleosome core particle revealed that core histone proteins can be divided into three types of motifs: 1) the histone-fold region, 2) their diverse extensions, and 3) the histone tails [reviewed in (9)]. The histone tails are regions that reach outside the nucleosome core particle. In contrast to highly structured histone folds, histone tails generally appear to be flexible and irregular chains. With the exception of H2A, which has tails on both sides of its well-ordered histone-fold region, tails of all of the other histones are amino terminal to the histone-fold domain. The tails account for approximately 28% of the core histone sequences overall and are extremely basic because of the high proportion of lysine and arginine amino acids in these regions.

The crystal structure of the nucleosome core particle shows that the basic histone tails are extended outside the histone fold and may interact weakly with DNA [reviewed in (9)]. However, these interactions may be too weak to contribute substantially to the stability of the nucleosome core, as judged from biophysical studies. Therefore, it is not likely that acetylation of a few basic lysine residues in the histone tails can release the inhibitory effect of chromatin on transcription by simply weakening the histone-DNA interaction or by introducing gross changes in the structure of nucleosomes. Alternative mechanisms have been proposed. First, acetylation may facilitate the binding of some transcription factors to the promoter. Deacetylated histone tails appear to inhibit access of some transcription factors to nucleosomal DNA as acetylation or truncation of the tails facilitates their binding (10-12). Second, acetylation may facilitate the disruption of higher order chromosome structure. In the crystal structure, the amino terminal tails of histones H3, H4, and H2A contact the histone octamer surface of neighboring nucleosome particles. For example, amino acids 16-24 of histone H4 interact extensively with the acidic region formed by H2A and H2B on the surface of the next histone octamer. The amino terminal residues of H4 as well as the acidic residues from H2A and H2B that form the only acidic patch on the core nucleosome structure are highly conserved, which suggested that such interaction is functionally relevant in vivo. Therefore, histone tails may be involved in the formation of higher order chromatin structure. Acetylation of H3 and H4 tails may thus disrupt higher order structure rather than destabilizing the histone-DNA interaction within the nucleosome. It is possible that histone acetylation has multiple effects on chromosome structure, which together lead to a "relaxed" chromosome template so that transcription can occur.

Two independent lines of early evidence further suggest that the association between acetylation and transcription may be mechanistically and physiologically relevant. First, yeast cells unable to acetylate the histone H4 tail because of mutation in the target lysine residues show altered patterns of transcription (13). Second, treatment of mammalian cells with potent inhibitors of histone deacetylase activity, such as trapoxin and trichostatin A, resulted in increased expression of a variety of genes [reviewed in (14)]. However, the molecular mechanisms underlying these observations were not known until the last 2 years, when a large number of histone acetyltransferases and histone deacetylases were identified. What is interesting is that a lot of these enzymes were originally described as proteins involved in transcriptional regulation.


    HISTONE ACETYLATION AND TRANSCRIPTIONAL ACTIVATION
 Top
 Abstract
 Chromosome Structure and...
 Histone Acetylation and...
 Histone Deacetylation and...
 Other Chromosome-Remodeling...
 A General Model of...
 Connection Between Chromosome...
 References
 
A number of histone acetylases have been identified during the past 3 years. They are quite diverse in terms of their enzymatic activity and regulation. The major known histone acetylases are described below.

p300/CBP is the first of such proteins that were initially implicated in transcription and that were then shown to enzymatically modify histones [reviewed in (15)]. CBP (CREB-binding protein) was originally cloned as a coactivator for the transcription factor CREB [cyclic adenosine monophosphate response element-binding protein (16)]. p300 was initially cloned by its association with the viral oncoprotein E1A, which is required for the full transforming phenotype of adenovirus (17). p300 and CBP are extremely similar both structurally and functionally. Both can bind CREB and E1A. Besides CREB, a large number of transcription factors were shown to recruit p300/CBP to activate transcription. The cloning of a p300/CBP-binding protein, p/CAF, provided the first hint for how p300/CBP activates transcription (18). P/CAF is structurally similar to the GCN5 protein from yeast and tetrahymena, which has been shown to have histone acetylase activity. The true human homologue of the yeast GCN5 appears to be hGCN5 (19); however, as will be discussed below, p/CAF and the complex containing hGCN5 have similar subunit compositions. The fact that adenovirus E1A protein disrupts the interaction between p/CAF and p300/CBP suggests that p/CAF is likely to be relevant for p300/CBP function in vivo(18). Later on, it was demonstrated that p300/CBP itself also has histone acetylase activity (20,21). Therefore, a complex containing multiple histone acetylases is brought to specific promoter elements by some transcription factors to activate transcription. What makes things more complicated is that p300/CBP is also found to be associated with the pol II holoenzyme (22), which suggests that p300/CBP has a more general function in transcription.

Two other transcriptional coactivators have also been demonstrated to be histone acetylases, ACTR (activator of the thyroid and retinoic acid receptor) and SRC-1 (steroid receptor coactivator). Both of them are involved in transcriptional activation by a variety of ligand bound nuclear hormone receptors [(23,24); reviewed in (25)]. The p/CAF histone acetylase and p300/CBP are also shown to bind to both ACTR and SRC-1. Therefore, similar to the p300/CBP-p/CAF complex, multiple histone acetylases are brought to the promoter by hormone receptors to activate transcription in a ligand-dependent fashion. The reason why multiple histone acetylases are required for activation is not yet clear. The fact that the histone acetylase domains of ACTR/SRC-1 do not share apparent homology with other histone acetylases may suggest that they have different substrate specificity; therefore, multiple enzymes are assembled together to achieve acetylation of different core histones.

Another transcriptional coactivator that has intrinsic histone acetylase activity is TAF250 (26), which is a component of the TBP-TAF (TBP-associated factors) complex. TAFs have been previously implicated to be targets of various transcription factors. Recent experiments show that TAFs are not generally needed for transcription; instead, they may be required for expression of only a subset of genes [reviewed in (27)]. Two recent studies (28,29) showed that a number of components of the TAF250 complex are shared by the p/CAF and GCN5 complexes. In yeast, the SAGA (Spt-Ada-GCN5-acetyltransferase) complex, which contains the GCN5 histone acetylase, also contains the histone-like TAFs (yTAF20, yTAF60, and yTAF68) (28). The histone-like TAFs have been previously shown to be associated with yTAF130 (yeast homologue of human TAF250). The human p/CAF complex also contains the histone-like TAFs (hTAFII 31 and hTAFII 20/15). In addition, two other proteins in the p/CAF complex are similar to hTAFII 80 and hTAFII 100 (28). Human cells contain a distinct complex that is similar to the p/CAF complex, hGCN5 (29). The compositions of hGCN5 and p/CAF are remarkably similar. Therefore, both the human hGCN5 and p/CAF complexes appear to be structurally and functionally homologous to the yeast SAGA complex. However, these TAF-containing SAGA or p/CAF complexes are not part of the regular TFIID (TBP-TAF) complex.

These results illustrate the complex nature of protein factors that acetylate histones. It then appears that multiple, diverse histone acetylase complexes exist, the p300/CBP-p/CAF complex, the p/CAF-hGCN5 complex, the SRC-1/ACTR-p/CAF-p300/CBP complex, and the TAF250 complex. Among these complexes, the counterparts of TAF250 and p/CAF-hGCN5 complexes are conserved in yeast, whereas the p300/CBP and SRC-1/ACTR histone acetylases appear to be absent in yeast. It is still not clear why there are so many different histone acetylase complexes. Many questions remain; for example, can they acetylate all core histones? Are all of them required for the transcription of a particular gene, or are they specific for different genes? Since p300/CBP, p/CAF, and TAF250 have been shown to acetylate non-histone proteins, such as transcription factor p53 and some general transcription factors (30,31), then do they have the same substrate specificity toward these non-histone proteins?

The in vivo roles of at least one of the histone acetylases have been demonstrated recently. Detailed mutation studies of GCN5 in yeast strongly suggest that histones are physiologically relevant substrates for histone acetylases. Furthermore, histone acetylase activity is critical for transcriptional regulation (32,33). In one of these studies (33), histone acetylation by various GCN5 derivatives was performed on nucleosomal templates. In the other study (32), the acetylation state of chromatin in yeast cells was analyzed. Of most interest was the finding that GCN5 increases histone acetylation at promoter regions in a manner that is related to GCN5-dependent transcriptional activation and histone acetylase activity in vitro(32). These studies suggest that there is a strict association between histone acetylase activity in vitro and transcriptional activity in vivo. However, the authors did not look at histone acetylation in promoters resistant to GCN5 activity.


    HISTONE DEACETYLATION AND TRANSCRIPTIONAL REPRESSION
 Top
 Abstract
 Chromosome Structure and...
 Histone Acetylation and...
 Histone Deacetylation and...
 Other Chromosome-Remodeling...
 A General Model of...
 Connection Between Chromosome...
 References
 
Since histone acetylation promotes transcription, it is not surprising to find that histone deacetylases are involved in transcriptional repression. It has been known for about two decades that a number of reagents can cause hyperacetylation of histones [reviewed in (14)]. These reagents include sodium butyrate and the microbial products trichostatin A and trapoxin. The effective concentration for sodium butyrate to cause histone hyperacetylation is in the millimolar range, which may have nonspecific effects on cellular function. However, trichostatin A and trapoxin are so effective that a nanomolar concentration is sufficient to cause hyperacetylation of histones. Trichostatin A appears to be a reversible inhibitor of histone deacetylase activity, whereas trapoxin irreversibly inhibits histone deacetylase. These histone deacetylase inhibitors can arrest the cell cycle and can cause differentiation of some cell lines. The mechanisms underlying these profound effects are not understood, and the connection between their ability to inhibit histone deacetylases and their effect on the cell cycle is not yet demonstrated.

The human HDAC1 was cloned by its affinity to one of the known histone deacetylase inhibitors, trapoxin (34). Like acetylases, histone deacetylases are also highly conserved across species. HDAC1 has sequence similarity to a yeast protein, Rpd3, which has been implicated in transcriptional regulation. HDAC/Rpd3 is found in complex with other proteins, particularly some well-known (co)repressors, such as Sin3 and the retinoblastoma protein (35-42). These corepressors are brought to DNA by different, yet specific, DNA-binding transcription factors, such as mad, unliganded nuclear hormone receptors, and E2F. The recent discovery that histone deacetylases are involved in transcriptional repression by methylation of CpG islands further demonstrated that histone deacetylation is a common mechanism for repression. CpG methylation has long been linked to gene silencing, and Mecp2, a protein that specifically binds to methylated CpG, has been shown to be important for CpG silencing. Now it turns out that Mecp2 recruits Sin3 and histone deacetylases to repression transcription (43,44). Therefore, a general theme of repressor complex assembly has emerged: A DNA-binding protein (Mad, E2F, etc.) recruits a corepressor (Sin3 or Rb), which in turn recruits histone deacetylases. One exception to this three-component model is the YY1 protein. YY1 is a DNA-binding transcription factor that can either activate or repress transcription (45). Its repressor activity largely depends on its association with any one of the three histone deacetylases. It has been demonstrated that the interaction between YY1 and histone deacetylases is direct (46). The Sin3 protein has not been reported to be involved in bridging YY1 and histone deacetylase.

It is also interesting that most of the DNA sequences where histone deacetylase complexes assemble may have opposite transcriptional regulatory functions. These sequences alternate between enhancers and silencers, depending on whether a histone acetylase complex or a histone deacetylase complex is assembled on this site. For example, when free E2F binds to an E2F site, it activates transcription at least partially by recruiting a p300/CBP complex (47). However, when Rb is activated, it binds to E2F and recruits a histone deacetylase to repress transcription; however, Rb does not appear to require histone deacetylase activity to inactivate E2F in in vitro transcription assays (48). Then it appears that there is a common scheme of transcriptional regulation in which alternative activation and repression achieve precise control of gene expression.

HDAC/Rpd3 proteins have been found in a variety of eukaryotes, and there are typically multiple family members in each organism (e.g., there are three known histone deacetylases in humans). Recently, another histone deacetylase has been identified in maize that has no sequence similarity to HDAC/Rpd3 (49). It may represent a new class of histone deacetylases with potentially distinct functions. All of the three human histone deacetylases are expressed in various tissues examined (50). They do not appear to have a tissue-specific expression pattern. The activity of various histone deacetylases has been demonstrated on histones or nucleosomes in vitro. There has been no apparent substrate specificity reported among the three known human histone deacetylases. Hassig et al. (50) showed that the three human histone deacetylases deacetylate all four core histones equally well in vitro; however, it is still possible that they exhibit a different substrate specificity in vivo when histones are packaged into nucleosomes.

The fact that potent histone deacetylase inhibitors can release histone deacetylase-dependent repression suggests that the enzymatic activity of deacetylases is required for repression. A putative histone deacetylase domain has been identified by sequence comparison and mutational analysis (50,51). The enzymatic activity of histone deacetylases has been demonstrated to be important for transcriptional repression in vivo. Yeast strains lacking either Rpd3 or Hda1 (another histone deacetylase in yeast) show increased acetylation at lysine 5 and lysine 12 on histone H4 (52). In both mammalian and yeast systems, HDAC/Rpd3 mutants that are defective for deacetylase activity but still capable of binding the Sin3 protein have been shown to be defective for transcriptional repression (50,51). Indeed, some of these mutants act as dominant negatives, since they may displace endogenous wild-type Rpd3 from the Sin3 complex (51).


    OTHER CHROMOSOME-REMODELING COMPLEXES AND TRANSCRIPTION
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 Abstract
 Chromosome Structure and...
 Histone Acetylation and...
 Histone Deacetylation and...
 Other Chromosome-Remodeling...
 A General Model of...
 Connection Between Chromosome...
 References
 
Besides post-translational modification of histones by acetylation, a different kind of enzymatic activity has been proposed to participate in remodeling chromosome to regulate transcription. These chromosome-remodeling complexes contain adenosine triphosphatase (ATPase) activity that disrupts histone-DNA interaction. They include the SWI/SNF complex in yeast and its homologues in other higher eukaryotes, such as the BRG1 and Brm complexes. They have been shown to alter nucleosome structure and to facilitate transcription factor binding. A number of related complexes have been isolated from various organisms, such as the RSC (remodeling the structure of chromatin) from yeast and the NURF (nucleosome-remodeling factor) from Drosophila [reviewed in (53)]. These distinct complexes have different components and different properties, yet they all contain an SWI2/SNF2-related subunit that possesses ATPase/helicase activity. The mechanisms of how these different complexes function are not clear; however, progress made recently has begun to elucidate the mechanisms of these chromosome-remodeling complexes (54). The authors used an in vitro system to demonstrate that the hSWI/SNF complex acts by facilitating an exchange between normal and altered, more accessible, nucleosome conformations. They suggest that this exchange is reversible and is mediated by the same hSWI/SNF complex. Therefore, oscillation between the two states generates a window of opportunity for transcription factor to bind to DNA.

It has been generally believed that these ATP-driven chromosome-remodeling activities are distinct from histone acetylation and deacetylation. However, the latest data suggest that these activities may be more closely linked than we thought. Two recent studies (55,56) show that both nucleosome-remodeling and histone deacetylation activities exist in the same complex. Specifically, the authors used antibodies against HDAC1 and/or HDAC2 to purify proteins associated with histone deacetylases. They found that there appeared to be multiple HDAC1/2-containing complexes. Two proteins in one of such complexes are CHD-3 and CHD-4, two known SWI/SNF-like proteins that have ATP-dependent chromosome-remodeling activity. These two proteins are also known as Mi-2{alpha} and Mi-2ß, respectively, which were originally identified as the dermatomyositis-specific autoantigens. The authors showed that the ATP-dependent activity of CHD-3 and CHD-4 could enhance the histone deacetylase activity of HDAC1/2 on oligonucleosome substrates, while this activity is not required for HDAC1/2 to deacetylate free histones. This complex is named NRD or NuRD (nucleosome remodeling and histone deacetylase). It seems to be a paradox, since ATP-driven chromosome-remodeling activity has been thought to be involved in transcriptional activation, whereas histone deacetylases are involved in repression. However, the coupling of two activities may provide an efficient way to achieve transcriptional regulation, since one activity provides substrate for the other. An earlier observation that BRG1 or Brm interacts with the retinoblastoma protein may indicate that this coupling of two chromosome-remodeling activities is not unique. BRG1 and Brm have ATPase activity, and they are the major components of the mammalian SWI/SNF complex, while Rb has been shown to recruit histone deacetylases to repress transcription. Even though the mechanistic meaning of the association between Rb and BRG1/Brm is currently not clear, it is likely that this interaction is physiologically relevant, since BRG1 appears to be required for Rb to suppress cell growth (57). Therefore, the coupling of two distinct chromosome-remodeling activities may be a quite common mechanism to regulate transcription. It is interesting to speculate that histone acetyltransferase activity may also be coupled to certain ATP-driven chromosome-remodeling activities.


    A GENERAL MODEL OF TRANSCRIPTION REGULATION
 Top
 Abstract
 Chromosome Structure and...
 Histone Acetylation and...
 Histone Deacetylation and...
 Other Chromosome-Remodeling...
 A General Model of...
 Connection Between Chromosome...
 References
 
A long-proposed model regarding transcriptional activation is that transcription factors activate transcription by interacting with components of the basal transcription complex and thus recruiting the basal complex [reviewed in (58)]. Different transcription domains have been shown to bind to basal transcription factors such as TBP, TFIIB, TAFs, and so on. Direct recruitment of a component of the basal complex such as TBP to the promoter by a Gal4-TBP fusion bypassed the requirement of a transcriptional activator, suggesting that basal complex binding to the promoter is a limiting step in transcription. However, numerous observations in the past 2 years suggest that chromosome structure is also important for gene regulation and that a number of transcription factors recruit complexes containing either histone acetylase or deacetylases to activate or repress transcription. Then how do we reconcile these two models of transcriptional regulation?

It is possible that both mechanisms are needed to achieve transcriptional activation in vivo. Post-translational modification of histones such as acetylation may create a transcriptionally competent state. However, acetylation itself may be necessary, but it may not be sufficient to activate transcription. Therefore, transcription requires multiple steps. The first step is the remodeling of the chromosome, which may require the concerted effort of two distinct chromosome-remodeling activities (i.e., histone acetylase activity and ATP-driven chromosome-remodeling activity). The second step is the recruitment of the basal transcription complex by the interaction of transcriptional activation domains and components of the basal transcription complex. Then the question is how these histone acetylase complexes are recruited to DNA in the first place if the binding sites are blocked by nucleosomes. It appears that nucleosome formation is not totally random; it may have some sequence preference. It has been reported that, in yeast, activator-binding sites are usually nucleosome free, but TATA boxes are often found in or near nucleosomes (59). Therefore, it is possible that some transcription factor-binding sites are nucleosome free, so that they can readily bind to DNA. Then this class of activators can recruit histone acetylase complexes to DNA, which subsequently acetylate histones to make binding sites for other transcription factor or the basal complex more accessible. A second class of transcription factors then recruits the basal transcription complex to activate transcription. This phenomenon may explain, at least partially, why transcription factors usually have a synergistic effect in activating transcription. The fact that Gal4-TBP is sufficient to activate transcription may simply be due to the presence of TAF250, a histone acetylase, in the TFIID (TBP-TAF) complex. Therefore, the Gal4-TBP fusion is doing two jobs that are normally performed by two kinds of transcription factors. Then the question is why multiple histone acetylases are needed. TAF250 presumably is present in all TFIID complexes, but it is only required for expression of a subset of genes and TAF250 dependency is dependent on the promoter context. It is possible that TAF250 possesses functions different from those of other acetylases such as p300/CBP or GCN5.

The same two-step processes may also be true for transcriptional repression. While histone deacetylation is one mechanism of repression, a number of other repression mechanisms have been proposed previously [reviewed in (60)]. Even in reports that demonstrate the importance of histone deacetylase in transcription repression, a histone deacetylase-independent mechanism has been implicated (35,42). This mechanism is not well understood, but a few models have been proposed [reviewed in (60)]. Some repressors may bind directly to components of the basal complex, such as TBP and TFIIB, and may block the assembly of the basal complex (61). Other repressors may bind to transcriptional activation domains and prevent them from interacting with the basal transcription complex (62). It is possible that these two mechanisms are utilized in a promoter-dependent fashion. Sequences on some promoters may not favor nucleosome formation; therefore, a histone deacetylase-independent or direct inhibition mechanism may be the predominant way to repress transcription.


    CONNECTION BETWEEN CHROMOSOME REMODELING AND DISEASES
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 Abstract
 Chromosome Structure and...
 Histone Acetylation and...
 Histone Deacetylation and...
 Other Chromosome-Remodeling...
 A General Model of...
 Connection Between Chromosome...
 References
 
Chromatin structure is closely linked to gene expression; deregulation of chromosome-remodeling activity may thus interfere with many critical cellular processes, resulting in development of diseases. A classic example is the observation that DNA viral oncoproteins, such as adenovirus E1A, simian virus 40 large T antigen, and the papillomavirus E7 protein, bind to proteins like p300/CBP and Rb. This interaction disrupts normal functions of these cellular proteins that are all involved in remodeling the chromosome structure. The fact that a well-known tumor suppressor, retinoblastoma gene (Rb), is linked to histone deacetylation demonstrates the cancer-chromatin connection. Most Rb mutants found in tumors affect the pocket integrity, and the pocket is the region that binds to HDAC1. Therefore, mutant Rb is no longer able to recruit histone deacetylases to maintain a repressed chromosome structure. Another example is the discovery that, in certain patients with leukemia, a chromosomal translocation event occurs so that CBP is fused to the MOZ protein, which itself is also a histone acetylase. This translocation may affect the regulation of normal CBP or MOZ acetylase activity, and it leads to the Rubinstein-Taybi syndrome (63). In addition, an acute promyelocytic leukemia causing a chimeric mutant of the retinoic acid receptor was found to be associated with HDAC1 (64,65), and recent treatment of a patient with acute promyelocytic leukemia with a histone deacetylase inhibitor and retinoic acid re-induced remission (66). Moreover, mutations in hSNF5, a component of the human SWI/SNF complex, have recently been linked to the development of malignant rhabdoid tumors (67). Finally, the recent finding that the NRD complex contains proteins linked to dermatomyositis development (55,56) further demonstrates the broad spectrum of diseases associated with deregulation of chromosome structure. It can be anticipated that more and more components of different chromatin-remodeling complexes will be linked to diseases one way or the other. Complete understanding of the mechanisms of how deregulation of chromosome structure leads to diseases may eventually help in the development of new therapeutic approaches.


    REFERENCES
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 Abstract
 Chromosome Structure and...
 Histone Acetylation and...
 Histone Deacetylation and...
 Other Chromosome-Remodeling...
 A General Model of...
 Connection Between Chromosome...
 References
 

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Manuscript received December 28, 1998; revised May 7, 1999; accepted June 8, 1999.


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