Human Molecular Genetics, 2001, Vol. 10, No. 20 2233-2242
© 2001 Oxford University Press
Human diseases with underlying defects in chromatin structure and modification
Centre for Genome Research, University of Edinburgh, Roger Land Building, Edinburgh EH9 3JQ, Scotland, UK and 1MRC Human Genetics Unit, Crewe Road, Edinburgh EH4 2XU, Scotland, UK
Received July 6, 2001; Accepted July 16, 2001.
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ABSTRACT |
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 TOP ABSTRACT DISORDERS OF CHROMATIN-MEDIATED...DISORDERS OF CHROMATIN...ARE THERE COMMON FEATURES...CHROMATIN DISEASES: WHAT HAVE...REFERENCES |
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Chromatin structure is important for regulating gene expression and for the proper condensation and segregation of chromosomes during cell division. Several human genetic diseases have been found to be due to mutations in genes producing proteins known or suspected to be involved in maintaining or modifying chromatin structure. Here we describe these ‘chromatin diseases’ and review what is known about the associated chromatin proteins in light of recent advances in the understanding of chromatin components, modification and function.
Failure of correct gene expression underlies many human genetic disorders. Altered expression of a single gene can result, for example, from deletion of that gene, from promoter mutations that alter its transcription, or from mutations that affect splicing or other levels of mRNA processing. Mutation of transcription factors also alters gene expression, and the phenotypic consequence of this will usually be felt by more than one target gene, and so tend to result in syndromes in which several different biological systems are disturbed. It is now widely appreciated that, as well as simple transcription factor binding, the modification of DNA and chromatin is integral to the correct control of gene expression in mammals (Figures 1 and 2). Therefore one would expect that there are genetic diseases in humans that result from mutations in the components of chromatin or in the enzymes that modify chromatin structure. If so, what are the consequences for gene expression and human development, and does understanding these diseases as disorders of chromatin (‘chromatin diseases’) inform us either about chromatin-based mechanisms of gene expression themselves or about ways in which the disease phenotypes might be ameliorated?
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The levels at which chromatin structure can be modified are complex. Gene silencing has been correlated with the establishment of repressive chromatin structures and the presence of large complexes that include histone deacetylases (HDACs). Repression complexes are often recruited by the presence of DNA methylation and by the proteins that recognize methylated CpGs in mammalian DNA. Conversely, the activation of gene expression can depend on the recruitment of chromatin complexes containing enzymes that can modify histones, for example via acetylation (histone acetyltransferases, HATs). Below we discuss examples where we think that these mechanisms of chromatin modification are aberrant.
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DISORDERS OF CHROMATIN-MEDIATED REPRESSION? |
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ATR-X syndrome: a defect in the organization of repressive chromatin?
The
-thalassemia/mental retardation syndrome, X-linked (ATR-X syndrome; OMIM 301040), Juberg–Marsidi syndrome (OMIM 309590), Sutherland–Haan syndrome (OMIM 309470) and Smith–Fineman–Myers syndrome (OMIM 309580) have all been shown to result from mutations in the ATRX gene (1–4) located at Xq13. Mutations of this gene invariably give rise to mental retardation and can also result in facial and skeletal abnormalities, urogenital abnormalities, mild -thalassemia and microcephaly. The initial reasons for believing that ATR-X syndrome might be a chromatin disease were primarily based on the observation that the ATRX protein had sequence similarity to known chromatin proteins. ATRX encodes a putative ATP-dependent type II helicase of the SNF2 family which is widely expressed in development (5,6). The function of this protein is not yet known, but it is capable of interacting with two different heterochromatin proteins, mHP1 and EZH2 (7,8). Further, ATRX is concentrated at pericentromeric heterochromatin in human and murine cells (9). The N-terminal part of the protein, containing PHD-type zinc finger and heterochromatin protein-interacting domains, appears to be sufficient for this localization. In human cell lines, ATRX is also associated with the short arms of human ribosomal DNA (rDNA) carrying acrocentric chromosomes (9). Most ATRX mutations affect the PHD-like domain of the protein (10). Evidence of perturbed chromatin was recently identified where the ATRX protein is known to normally reside: repetitive DNA (11). The fact that ATRX locates at arrays of rDNA led Gibbons et al. (11) to investigate the chromatin structure of this type of DNA. Though no changes in DNase I hypersensitivity could be detected, they did find that the rDNA genes in ATR-X patients were substantially undermethylated compared with normal individuals. This led them to investigate the methylation status of other kinds of repetitive DNA sequences. Two further sequences were identified which showed changes in DNA methylation in ATR-X patients. However, in contrast to the rDNA repeats, a Y chromosome-specific repeat (DYZ2) showed higher DNA methylation levels in ATR-X patients than normal, whereas it was unclear whether the methylation was increased or decreased in the TelBam3.4 repeats (11).
How does mutation of a putative chromatin-remodelling protein lead to altered DNA methylation? ATRX itself is not thought to have any DNA methyltransferase activity; therefore it is most likely that its mutation alters the recruitment of a methyltransferase (de novo or maintenance?) to repetitive sequences (Fig. 1). In Arabidopsis thaliana, loss of function of a SWI2/SNF2-like protein (DDM1) similarly leads to hypomethylation of repetitive sequences, but also to a detectable overall reduction (70%) in bulk genomic methylation (12). The consequences of this global hypomethylation are the mobilization of transposable elements (13). This scenario seems unlikely to be happening in the cells of ATR-X patients, since the total amount of 5-methylcytosine in ATR-X cells appears to be normal (11).
It is tempting to speculate that it is the methylation changes in ATRX deficient cells that lead directly to the misexpression of a number of genes resulting in the phenotypes associated with ATR-X syndrome. Yet DNA methylation changes have only been detected thus far in repetitive sequences. No methylation changes have been detected in single copy genes, not even at the one gene known to be misexpressed in ATR-X syndrome, the -globin gene (11). In contrast, it is currently not known whether gene expression is altered in the one place hypomethylation has been found in these cells, the rDNA repeats. The use of DNA microarrays may help to identify other candidate target genes to assess for methylation changes.
However, ATR-X syndrome may not be caused simply by DNA methylation-induced changes in gene expression. By analogy with Mi-2, to which it is related (14), ATRX might be part of a large protein repression complex that modulates gene expression by, for example, the recruitment of HDACs (15,16). The absence of this hypothetical ATRX complex might result in the observed perturbation of DNA methylation patterns in tandemly repeated sequences, but be unrelated to the disease pathology. Ideally further biochemical and functional studies of the ATRX protein will provide critical clues as to the nature of the chromatin defect in ATR-X syndrome.
ICF syndrome: the importance of DNA methylation
Whilst it is far from clear that the underlying defect in ATR-X syndrome is altered DNA methylation levels per se, changes in DNA methylation can have very severe consequences. Mice carrying a targeted mutation in Dnmt1, the gene encoding an enzyme responsible for maintaining DNA methylation levels, fail to develop to term (17). Global decreases in DNA methylation levels also cause developmental abnormalities in frogs (Xenopus laevis) (18) and in plants (A.thaliana) (19). In addition to DNMT1, mammals have two more proteins capable of methylating DNA, called DNMT3A and DNMT3B (20). Unlike DNMT1, which much prefers hemimethylated DNA as a substrate (21), both DNMT3A and DNMT3B only show methyltransferase activity on unmethylated DNA, and hence are considered to be de novo DNA methyltransferases (20) (Fig. 1). In 1999 the DNMT3B gene was mapped to human chromosome 20q11.2 (22,23), making it an excellent candidate for the gene responsible for ICF syndrome (OMIM 242860) (24).
ICF syndrome is a rare autosomal recessive disorder in which patients display immunodeficiency, instability of peri-centromeric heterochromatin of chromosomes 1, 9 and 16, and facial anomalies, as well as mental retardation and developmental delay (25). DNMT3B was such a likely candidate for the gene mutated in ICF syndrome because the pericentromeric instability seen in lymphocytes from ICF patients looks very similar to that seen when normal lymphocytes are treated with demethylating agents (26). This led Jeanpierre et al. (27) to compare the level of DNA methylation present in these heterochromatic sequences between ICF and normal lymphocyte DNAs. Sure enough, they found that classical satellite DNA is hypomethylated in ICF patients (27), and this has since been extended to include other types of repetitive DNA (28) as well as the inactive X chromosome (29,30). In 1999, three different groups reported that ICF syndrome is indeed caused by mutations in the DNMT3B gene (31–33). At the same time, hypomethylation of centromeric heterochromatin was reported in mice homozygous for a targeted mutation in Dnmt3b (32). The spectrum of mutations identified in ICF patients, predominantly missense mutations in the C-terminal catalytic domain, is predicted to interfere with, but not to completely abolish, the methyltransferase enzymatic activity (34). Consistent with this, deletion of the Dnmt3b catalytic domain in mice invariably results in prenatal lethality (32).
That ICF syndrome it is a disorder of chromatin organization can hardly be questioned. It results from mutations in a core component of the chromatin modifying machinery, and both decreased DNA methylation levels and an increase in DNase I hypersensitvity (a general measure of the degree of chromatin compaction) have been documented in cells derived from ICF patients (27,30). So how does this alteration of chromatin structure result in the various phenotypes of ICF syndrome?
The first place to look is in the structure of the chromosomes themselves. Whilst demethylation of satellite DNA is present in multiple cell types from ICF individuals (27), chromatin undercondensation and chromosome breakage/instability are principally documented in T lymphocytes stimulated to divide in culture. There is some evidence to suggest that there is also chromosome breakage in blood cells in vivo, but there are no signs of chromosome instability in other cell types such as fibroblasts (35). It is not clear why lymphocytes should be especially prone to unravelling of undermethylated pericentric heterochromatin. Perhaps some lymphocyte-specific factor [Ikaros? (36)] is recruited to methylated heterochromatin and is necessary for its correct condensation. This factor may also be required for proper gene silencing in lymphocyte lineages, contributing to the immunodeficiencies and susceptibility to infections that are seen in ICF patients. It is important to note that there have been no reports of undercondensed or unstable chromatin at the chromosomal locations shown to be hypomethylated in ATR-X cells, nor is immunodeficiency found in ATR-X patients.
Does a failure of proper DNA methylation in ICF syndrome also lead to misexpression of key genes that perturb cranio-facial, cerebral and immunological development? While Hansen et al. (30) have recently demonstrated misexpression of genes normally silenced by X chromosome inactivation in cells derived from ICF patients, the lack of gender-specific phenotypes in the ICF syndrome means that this is unlikely to be a major cause of pathology. However, they also demonstrated misexpression of the SYBL1 gene, which is located within the Xq/Yq pseudoautosomal region and is normally silenced on the inactive X chromosome in females and the Y chromosome in males (30,37). These findings demonstrate that normal silencing mechanisms are not functioning properly in cells derived from ICF patients, and thus it is reasonable to expect that, like SYBL1, certain autosomal genes may escape their normal transcriptional restraints in cells lacking a fully functional DNMT3B protein.
The subcellular localization of endogenous DNMT3B is not yet reported, but exogenously tagged protein co-localizes with pericentric heterochromatin in murine embryonic stem (ES) cells, even when DNA methylation levels are reduced to 
30% of normal levels (38). In contrast, the protein shows a more diffuse localization in murine fibroblasts. Therefore its nuclear location, and hence its activity, may be modulated during development. Recently it has been demonstrated that the N-terminal domain of DNMT3B, which is responsible for targeting the protein to pericentromeric sequences, is capable of interacting with HDACs and mediating transcriptional repression in vitro (38,39). In addition, the protein contains a PHD-like finger, most similar to that found in ATRX. This strengthens the idea that ATRX protein itself may function as part of a repressive complex. Neither the mutations described thus far in the ICF syndrome, nor the one Dnmt3b targeted mutation engineered in mice, affect the integrity of the N-terminal domain, so the in vivo requirement of the silencing and localization ability remains to be determined.
Rett syndrome (RTT): interpreting DNA methylation
The presence of DNA methylation itself can influence transcription (40,41). One mechanism through which this influence is achieved involves the recognition of methylated DNA by methyl-CpG binding proteins, which then recruit co-repressor complexes containing HDAC activity to repress transcription (42) (Fig. 1). Three such methyl-CpG binding proteins have been described in mammals: MeCP2, MBD1 and MBD2 (43,44). Though each of these proteins is capable of binding to a single symmetrically methylated CpG site in vitro (45,46), they show distinct binding patterns in chromosomal DNA (45,47). They also differ in the identity of the co-repressor complex with which they interact (47–50). If cytosine methylation is a way of putting a signal onto DNA, then the presence of at least three different methyl-CpG binding proteins, each with different binding patterns and repression partners, suggests that this signal can be interpreted in several different and potentially complex ways.
As detailed above, mutations in proteins involved in maintaining chromatin organization and in the process of DNA methylation can have severe consequences for humans and for mice. That the interpretation of the DNA methylation signal is just as important was demonstrated when the human neurodevelopmental disorder RTT was shown to be caused by mutations in the gene at Xq28 that encodes MeCP2 (51) (OMIM 312750). Classical RTT patients develop seemingly normally for 6–18 months; however, this is followed by a period of regression characterized by a deceleration in head growth, loss of speech and purposeful hand use, and the appearance of repetitive hand movements. Patients can also suffer from autism, apraxia and severe breathing dysfunction (52). After this initial period of regression, the condition becomes more stable and many survive into adulthood. RTT is now known to be one of the most predominant causes of mental retardation in females, occurring with a frequency of up to 1/10 000 live female births (53).
The vast majority of RTT cases are females heterozygous for mutations in the X-linked MECP2 gene. Because of random X chromosome inactivation, half of the cells in these females should express only the normal MeCP2 allele, while half express only the mutant allele. Mutations in essential X-linked genes often lead to non-random (or skewed) X chromosome inactivation. This is the case for females heterozygous for a mutation in the ATRX gene, for example (54), but does not appear to be the case for most females carrying a mutation in one of their MECP2 alleles (55). However, obligate carriers of MECP2 mutations, who present as normal females or who exhibit only mild phenotypes, were presumably saved from suffering RTT because they fortuitously silenced the mutation-bearing X chromosome in the majority of their cells (56–58), or at least the majority of their neurons (see below).
The result of MeCP2 mutation in mice is remarkably similar to the human situation. Female mice heterozygous for a deletion of Mecp2 appear completely normal for the first few months of life and are capable of mating and caring for their offspring. At 6 months, however, they begin to develop RTT-like symptoms including irregular gait, breathing abnormalities and decreased movement (59). As in RTT, this period of regression is followed by stabilization of the phenotype, and the mice can live for >18 months—a respectable mouse life-span. Thus female mice heterozygous for a mutation in Mecp2 develop a RTT-like phenotype at the same amount of time after birth as do humans (59). This indicates that the duration of the period of seemingly normal development preceding the inevitable descent into RTT-like behaviour for both humans and mice is measured in real time, rather than developmental time. This is a completely unexpected conclusion given the radical difference in the timing of developmental programmes between the two species.
Males inheriting a MECP2 mutation would be hemizygous for the mutant allele and, until recently, were predicted to die pre- or perinatally (60). Though some affected males born into families with recurrent RTT have been described (61,62), the only male patients with ‘classic’ RTT have been found to carry an extra X chromosome (58,63). However, recent data are casting doubt on this assertion. Wan et al. (64) found an MECP2 mutation in the brother of two ‘classical Rett’ sisters, though this boy died of apnea at only 5 days of age (61). Similarly, Hoffbuhr et al. (58) recently described a truncating MECP2 mutation in a boy with acquired microcephaly who died at 21 months of respiratory failure. If we now accept that being hemizygous for a MECP2 mutation does not necessarily result in pre- or perinatal lethality (65), then why haven’t more males harbouring such mutations been found? Two major reasons can explain this discrepancy. First, the boys are probably not being identified; since the phenotype of males hemizygous for MECP2 mutations is so much more severe than is seen in RTT females, paediatricians wouldn’t previously have thought to check a hypotonic baby boy with respiratory problems and severe, neonatal-onset encephalopathy for mutations in MECP2. Secondly, the vast majority of de novo RTT-causing mutations arise on paternal X chromosomes (66,67), and so are inherited only by females or males with Klinefelter’s syndrome. Therefore, the number of males inheriting a mutated MECP2 gene will be significantly less than the number of females inheriting such a mutation.
Like boys born with MECP2 mutations, mice lacking a functional Mecp2 gene appear completely normal at birth. Yet unlike their human counterparts, Mecp2-knockout mice remain of normal appearance for the first 4–6 weeks of life. After this initial period of normalcy, these mice experience a period of rapid regression resulting in death at 8 weeks (59,68). A decrease in the size of the brain as well as the sizes of a subset of neurons has also been described in these mice after 3–4 weeks of age (68), mimicking the situation reported for RTT girls (69). It is not yet known whether the few males described with RTT-causing MeCP2 mutations also show reduced neuronal size, though encephalopathy is a common feature in these boys (see above).
In murine nuclei, MeCP2 protein is concentrated in the regions of repetitive DNA that harbour the highest concentrations of methylated CpGs. Its distribution in human nuclei appears to be more widespread. RTT-causing missense mutations (http://www.ed.ac.uk/~skirmis/) are found both in the domain of the protein that is responsible for binding to methyl CpG (the MBD), and the domain of the protein that mediates transcriptional repression (TRD) by recruiting a co-repressor complex containing mSin3A and HDAC activity (70) (Fig. 1). Hence, it is reasonable to assume that aberrant patterns of gene expression might result in RTT, either because of the failure of MECP2 to bind to the correct genomic sites (mutations of the MBD) causing failure to recruit repression complexes there, or because the mutant protein is able to bind to methyl-CpG but unable to recruit the HDAC-containing repression complex (mutations in the TRD). In support of this, a global increase in the amount of acetylated histone H4 has been documented in cell lines derived from RTT patients who fail to produce MECP2 (71).
In the 2 years since the link between MECP2 and RTT was first made, a number of other, more mild forms of X-linked mental retardation (XMR) in males have been reported to be caused by mutations in MECP2 (72–75). Whereas mutations causing classical RTT are most likely to be complete loss-of-function mutations (76,77), those causing XMR are predicted to be decidedly more subtle. Yet even these small changes are enough to result in an impairment of brain function, emphasizing the importance of the role played by MeCP2 in the brain.
Even though we know that MeCP2 binds to methylated chromatin (70), and we even know mechanisms it uses to repress transcription (48,49), we still do not know what the in vivo targets of this repression might be. MeCP2 is widely expressed, but it is especially abundant in the brain (70). Furthermore, mouse mutations suggest that this may be its main site of action. Mice in which Mecp2 deletion occurs predominantly in brain at embryonic day 12 have a phenotype indistinguishable to those lacking Mecp2 in every cell of the body (59,68). If Mecp2 is deleted only in post-mitotic central nervous system (CNS) neurons, the mice also develop a similar phenotype, although at a later age (68). These results indicate that disease is caused by a lack of MeCP2 in mature neurons. If this is true for humans as well as mice, then RTT may not be a neurodevelopmental disorder as has been believed, but rather a neurodegenerative disease.
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DISORDERS OF CHROMATIN ACTIVATION? |
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TOPABSTRACTDISORDERS OF CHROMATIN-MEDIATED...DISORDERS OF CHROMATIN...ARE THERE COMMON FEATURES...CHROMATIN DISEASES: WHAT HAVE...REFERENCES |
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Rubinstein–Taybi syndrome (RSTS): deficiency of a histone acetyl transferase?
Chromatin modification is involved not only in gene repression, but also in the activation of gene expression (Fig. 2). The acetylation of histones H3 and H4 has long been associated with transcriptional activity, and many proteins identified as transcriptional co-activators have HAT activity. RSTS is a congenital malformation and mental retardation syndrome that is inherited in an autosomal dominant manner. The malformations characteristic of RSTS include cardiac anomalies, broad thumbs and big toes, and characteristic facies (beaked nose) (OMIM 180849). Petrij et al. (78) showed that the minimal region defined by 16p13.3 breakpoints in RSTS individuals contained the gene for CREB-binding protein (CBP), and found point mutations within the gene. At the molecular level RSTS is most likely a haploinsufficiency of CBP function since 20% of mutations are deletions/microdeletions or protein-truncating mutations (79,80). The absence of consistent phenotypic differences between individuals with deletions, protein truncations or missense mutations argues against a dominant negative mechanism.
CBP is a HAT and can acetylate all of the core histones in vitro (81,82). However, it can also acetylate other proteins, including p53, and components of the basal transcription machinery (83,84). So is RSTS a chromatin disorder, i.e. are the phenotypes due to altered histone acetylation, to defective acetylation of other proteins, or to both? A suggestion that histone acetylation itself may be defective comes from HAT assays using versions of CBP carrying RSTS-associated mutations. The domain of CBP necessary for HAT activity (amino acids 1099–1758) was determined by generating truncations of mouse Cbp (81,82). Murata et al. (80) identified a missense mutation within the equivalent region of CBP in an RSTS individual, which changes a conserved arginine residue to proline. In in vitro assays they demonstrated that this amino acid change abolishes the HAT activity of the mutant protein, and its ability to transactivate CREB. This at least raises the possibility that the molecular defect in this individual might be a failure of histone acetylation; however, the ability of the mutant protein to acetylate other proteins was not assayed.
Yet again, there is a considerable gap between knowing what a chromatin modifying protein is capable of doing, and knowing what its physiologically relevant targets are. CBP has been the focus of intensive study because it is a transcriptional co-activator for many transcription factors, including cAMP-regulated gene expression and thyroid hormone receptor. In Drosophila, CBP is needed for the expression of dpp in the hedgehog signalling pathway (85). Because dpp is a homologue of mammalian bone morphogenetic protein (BMP) it has been suggested that the skeletal anomalies in RSTS are due to defective expression of Bmps. This is supported by the skeletal abnormalities and reduced Bmp7 expression in mice heterozygous for a knockout of Cbp (86).
Coffin–Lowry syndrome (CLS): an interface between signal transduction and chromatin modification
The case for considering CLS as a chromatin disease is less strong than that for RSTS. CLS is a form of XMR (Xp22.1–22.2) accompanied by characteristic facial dysmorphism, progressive skeletal deformation and abnormal digits, particularly bulbous but tapering fingers (OMIM 303600). Trivier et al. (87) showed that in CLS individuals there were deletion, nonsense and missense mutations in the gene encoding RSK2, part of a family of growth factor-regulated serine/threonine kinases acting distally in the ras-dependent MAPK signalling cascade. Activation of RSK by MAPK leads to RSK translocation from the cytoplasm to the nucleus where, presumably, it effects many of its functions. There is a genotype–phenotype correlation in CLS in that a significantly milder phenotype (e.g. mental retardation alone) can be found in individuals with missense mutations in RSK and residual kinase activity (88). Similarly, female carriers can also have learning disability, a mild facial phenotype and digit dysmorphism.
As is so often the case with kinases, it is very difficult to discern which of the potential targets/substrates for phosphorylation are the physiologically relevant ones. Mitogen stimulation of mammalian cells leads to rapid, but transient, phosphorylation of histone H3 on serine 10 (Fig. 2) (and also HMG14 phosphorylation). This is known as the nucleosomal response (89), and it is both mechanistically and temporally distinct from the ser10 phosphorylation of H3 that correlates with mitotic chromosome condensation. Sassone-Corsi et al. (90) suggested that RSK2 is required for phosphorylation of H3 during the nucleosomal response stimulated by epidermal growth factor (EGF) and they showed that purified RSK2 can phosphorylate H3 on Ser10 in vitro. This prompted them to ask whether cells from CLS individuals are deficient in this histone modification. An Epstein–Barr virus transformed fibroblast cell line (DX34), derived from a CLS patient in which a splice site mutation results in an unstable truncated RSK2 protein product, failed to exhibit EGF-stimulated phosphorylation of H3, although H3 was phosphorylated normally during mitosis. Introduction of wild-type RSK restored the activity. This suggested that, at least in this one cell line, there was a deficit specific to EGF signalling; other signalling pathways (e.g. serum stimulation) appeared normal.
This observation is strengthened by the cellular phenotype of murine ES cells with a disruption of Rsk2. These cells are also deficient in EGF-stimulated H3 phosphorylation (90). However, the effect of RSK on H3 phosphorylation could be direct or indirect and it is clear that H3 is not the sole target for phosphorylation by RSK. In the same way that CBP can acetylate transcription factors as well as histones, RSK can phosphorylate CREB (on Ser 133) and thereby activate it. RSK has also been reported to phosphorylate c-FOS protein, SRF, Nur77, and the oestrogen receptor, as well as acting to dampen the signalling pathway itself by phosphorylation of the ras GEF SOS (91).
How might a defect in H3 phosphorylation result in aberrant gene expression via a chromatin-mediated pathway? Several different modifications (acetylation, methylation and phosphorylation) can be present on the same histone molecules (92) (Fig. 2) and the presence of one can affect the others (93). Cheung et al. (94) have shown that EGF-stimulated phosphorylation of H3 is rapidly followed by increased levels of H3 acetylation, especially at the promoter of c-fos—an immediate early gene considered to be a target of RSK by Sassone-Corsi et al. (90) The specific HAT responsible for this acetylation has not been identified. However, the fact that RSK2 interacts with p300/CBP makes it tempting to speculate that whilst phosphorylating H3 at the c-fos promoter it may simultaneously recruit a HAT to bring about targeted acetylation there as well. In vitro assays also suggest that phosphorylated H3 might be a preferred substrate for HAT activity.
It is far from clear that a defect in H3 phosphorylation per se, rather than a loss of phosphorylation of other targets, contributes to any of the phenotypes of CLS individuals. The phenotype of CREB mutant fruit flies and mice suggests that loss of active (phosphorylated) CREB is a plausible explanation for some of the deficits in neurological function of CLS individuals (95). Clearly, other kinases, such as MSK1, are also capable of mediating H3 phosphorylation in interphase nuclei during the immediate-early response, and it will be important to assess their activity in CLS cells (89).
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ARE THERE COMMON FEATURES TO CHROMATIN DISEASES, AND ARE THERE OTHER CHROMATIN DISORDERS? |
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TOPABSTRACTDISORDERS OF CHROMATIN-MEDIATED...DISORDERS OF CHROMATIN...ARE THERE COMMON FEATURES...CHROMATIN DISEASES: WHAT HAVE...REFERENCES |
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As we have discussed above, constitutional defects in the chromatin components that cells use to silence or activate gene expression are found in human genetic disorders (Table 1). These can all manifest clinically as syndromes affecting multiple biological systems, probably a testament to the number and broad range of genes whose expression must be perturbed in these diseases. This collection of chromatin diseases that we already know about must surely be only scraping the surface of those that exist given, for example, the plethora of genes in the human genome encoding HATs and HDACs alone. We are also only just beginning to appreciate the impact that perturbing chromatin has on human genome function, and to understand a few of the chromatin-based mechanisms that mammalian cells use to silence or activate gene expression. It is possible that defects in higher-order chromatin structures and nuclear architecture may have roles in other diseases (96).
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One abiding question is why is mental retardation such a prominent feature of diseases linked to mutations in chromatin proteins? The trivial explanation is that brain function depends on the integrated actions of a diverse array of genes and so is most sensitive to the perturbation of mass gene expression. Alternatively, chromatin structure, and especially DNA methylation, might have a special role to play in regulating gene expression in neurons. Understanding this is especially important in light of the wider role for mild mutations in genes encoding chromatin proteins in non-syndromic mental retardation in the human population (74,88,97). Cranio-facial development also seems to be particularly susceptible to perturbation in diseases of chromatin components.
Mutations in chromatin components are also commonly involved in cancers, and can even involve the same components as those mutated in inherited syndromes. CBP, the gene mutated in RSTS, is commonly involved in acquired translocations associated with haematological malignancies (reviewed in 98). These translocations result in the production of novel fusion proteins which may, in turn, allow for inappropriate patterns of histone acetylation and hence gene activation. RSTS patients are themselves predisposed to developing cancers, but these tend to be neural and developmental tumours especially of the head, not haematological malignancies (99). p300, a HAT closely related to CBP, is also commonly mutated in cancers, but no constitutional mutations in p300 have been reported. What is perhaps surprising is that increased cancer risk has not been reported in the other syndromes that we have discussed, especially in ICF syndrome, where the chromosome instability found in lymphocytes might be thought to predispose to aneuploidy. Aberrant patterns of DNA methylation are also a common hallmark of tumours (100).
The pRb protein, with its long-standing and honourable pedigree as a tumour suppressor, is now thought to exert some of its function through recruitment of HDACs. Proteins involved in other levels of chromatin structure and modification also have involvement in human cancers. These include proteins such as MLL (a homologue of Trithorax, a known chromatin organizer protein in Drosophila) and the SWI/SNF chromatin remodelling proteins. Both alleles of the gene encoding the chromatin remodelling component hSNF5/INI1 are mutated in the aggressive malignant rhabdoid tumour (MRT) (101). Constitutional loss-of-function mutations of this gene have been detected in families prone to renal or extrarenal MRT and to a variety of tumours of the CNS (102). Mice heterozygous for a Snf5/Ini1 loss of function are also cancer-prone (103).
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CHROMATIN DISEASES: WHAT HAVE THEY TOLD US, AND WHAT CAN WE DO? |
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TOPABSTRACTDISORDERS OF CHROMATIN-MEDIATED...DISORDERS OF CHROMATIN...ARE THERE COMMON FEATURES...CHROMATIN DISEASES: WHAT HAVE...REFERENCES |
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A recurring problem in studying chromatin proteins has been that, whilst it has been possible to quite readily demonstrate activities that these proteins can have, it has generally not been possible to determine which of these activities, if any, are really relevant in vivo. The detailed cellular and biological phenotypes of individuals with mutations in genes encoding chromatin proteins, combined with the study of targeted mutations in animal models, is going to be absolutely critical in elucidating the physiological targets of chromatin proteins. Hopefully, knowing these targets will in turn contribute to designing rational approaches to treat these disorders. The first signs of this occurring are in the strategies being employed to treat certain cancers. In acute promyelocytic leukaemia (PML) the PML protein is fused to the domain of the retinoic acid receptor (RAR) which interacts indirectly with an HDAC. The assumption is that this results in HDAC activity being recruited to inappropriate sites in chromatin via PML, resulting in aberrant histone deacetylation and gene repression (104). Addition of trans-retinoic acid prevents the interaction of the RAR portion of the fusion protein with HDAC and this treatment can successfully lead to remission of acute PML in some cases (104). Now, chemical inhibitors of HDACs are being used in the treatment of this and other forms of acute myeloid leukaemia (105). Such broad specificity inhibitors are a blunt instrument but they represent starting points from which to develop more specific and targeted reagents.
The various ways of modifiying chromatin structure discussed above provide a myriad of possibilities for how the instructions encoded in the DNA can be interpreted (Figs 1 and 2). The modulation of chromatin provides a means for certain instructions to be completely hidden from view, and for others to be thrust into the limelight. The timing and action of the various repressors and activators, methylators and acetylators, condensors and remodellers, is a complex choreography that plays with flawless precision in most of our cells day in and day out. Yet as we have seen, it only takes a defect in one of the many players to disrupt the whole process. Hopefully by studying these players we can better understand chromatin and how it functions, and hence have a better understanding of how to deal with the problems arising when chromatin organization goes awry.
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ACKNOWLEDGEMENTS |
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We thank Alison Kerr, Carolyn Schanen, David FitzPatrick, Maurizio D’Esposito and Adrian Bird for useful discussions and Robin Allshire for critical reading of the manuscript. B.H. is funded by the Wellcome Trust and W.B. is funded by the MRC and the James S. McDonnell Foundation.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +44 131 650 5890; Fax: +44 131 650 7773; Email: brian.hendrich@ed.ac.uk Correspondence may also be addressed to W.Bickmore. Tel: +44 131 332 2471; Fax: +44 131 343 2620; Email: w.bickmore@hgu.mrc.ac.uk
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TOPABSTRACTDISORDERS OF CHROMATIN-MEDIATED...DISORDERS OF CHROMATIN...ARE THERE COMMON FEATURES...CHROMATIN DISEASES: WHAT HAVE...REFERENCES |
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