Human Molecular Genetics Advance Access originally published online on August 19, 2003
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Human Molecular Genetics, 2003, Vol. 12, Review Issue 2 R221-R227
DOI: 10.1093/hmg/ddg286
© 2003 Oxford University Press
DNA methylation and Rett syndrome
Wellcome Trust Centre for Cell Biology, University of Edinburgh, The King's Buildings, Edinburgh EH9 3JR, Scotland, UK
Received August 8, 2003; Accepted August 13, 2003
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ABSTRACT |
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ABSTRACT
DNA METHYLATIONMethylation of cytosine in human DNA has been studied for over 60 years, but has only recently been confirmed as an important player in human disease. Rett syndrome is a neurological disorder caused by mutations in the MeCP2 protein, which has been shown to bind methylated DNA and repress transcription. This review will focus on experiments addressing the basic properties of MeCP2 and on mouse models of Rett syndrome that are starting to yield insights into this condition.
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DNA METHYLATION |
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DNA methylation is probably universal in vertebrates. In humans, approximately 1% of DNA bases are modified postsynthetically by addition of a methyl group to carbon-5 of the cytosine pyrimidine ring, predominantly at CpG dinucleotides. In mammalian cells, methylated CpGs are dispersed throughout the genome, but the majority are located in transcribed regions and intergenic DNA. Exceptions to this generalization are CpG islands, which are mostly methylation-free. CpG islands contain high densities of the CpG dinucleotide and are found at the promoter regions of about 60% of human genes that are transcribed by RNA polymerase II (1,2). In atypical cases, where CpG islands become methylated during development, modification is important for stable silencing of the associated gene. For example, failure to methylate CpG islands on the inactive X chromosome (Xi) leads to leaky repression of Xi-linked genes (3,4).
The methylation mark can affect gene expression in two ways. The first mechanism involves direct interference of methyl-CpG with the DNA binding of transcription factors. For example, the transcription factor Ets-1 or the boundary element factor CTCF, bind non-methylated but not methylated sites (5,6). The second mechanism involves a group of proteins which bind methylated CpGs independent of their DNA sequence context. Currently there are five known mammalian proteins which bind methylated CpG. Four of these, MeCP2, MBD1, MBD2 and MBD4, have related DNA binding domains (7). A fifth unrelated protein, Kaiso, requires two symmetrically methylated CpGs for binding (8). Four of the five proteins can repress transcription from methylated promoters in model experiments (the exception being MBD4 which is a DNA repair protein) (9).
Defects in the DNA methylation machinery are involved in human disease. Most directly, mutations in the de novo DNA methyltransferase DNMT3B result in reduced methylation of pericentromeric DNA sequences and cause a rare disorder called ICF syndrome. The symptoms of this condition are immunodeficiency, instability of pericentromeric heterochromatin, facial abnormalities and mental retardation (10). Most cancers also involve DNA methylation abnormalities, in particular unscheduled gene silencing via DNA methylation at CpG island promoters. This review concerns Rett syndrome, which is known to be caused by mutations in the gene for one of the methyl-CpG binding proteins, MeCP2 (11).
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RETT SYNDROME |
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Rett syndrome is a relatively frequent form of mental retardation and occurs sporadically once every 10 000–22 000 female births. It is characterized by a period of normal development until around 1 year followed by a rapid regression that involves loss of acquired speech and motor skills, microcephaly, seizures, autism, ataxia, intermittent hyperventilation and stereotypic hand movements (12–15). Despite these symptoms, patients often survive into adulthood. Several recent studies show that, after the initial crisis associated with symptom onset, there is no further regression, suggesting that the condition does not involve progressive neurodegeneration (16,17).
Rare familial Rett syndrome cases allowed mapping of the disease region to Xq28 (18), and screening of candidate genes in the region identified mutations in the MECP2 gene as frequent events in Rett patients (11). Later, extensive patient screening established that 
80% of Rett syndrome cases are associated with discernable mutations in the MECP2 gene. These mutations are, beyond reasonable doubt, the cause of Rett syndrome, as they are almost always absent (see below) in parents of the affected child.
Comprehensive databases of disease-causing MECP2 mutations and some apparently benign MECP2 polymorphisms have been compiled. A database at the University of Edinburgh (www.mecp2.org.uk) is primarily focused on collecting MECP2 mutations with detailed information about symptoms provided by parents and caregivers. Another database, RettBASE (http://mecp2.chw.edu.au/), collects information from laboratories and from paediatricians who screen for MECP2 mutations.
Most missense mutations in MECP2 that cause Rett syndrome are tightly clustered at the methyl-CpG binding domain (MBD; Fig. 1). Deletion/insertion mutations leading to loss of the open reading frame occur throughout the protein, but are clustered in the C-terminal region, which contains a poly-histidine repeat. Rett syndrome patients display a wide spectrum of mutations, but 67% of all mutations are in eight hot spots (R106, R133, T158, R168, R255, R270, R294 and R306). Seven out of eight major mutations affect arginine, which has a CpG in its codon. It is therefore likely that these mutations are due to unrepaired deamination of 5-methylcytosine which is responsible for about one-third of all point mutations that give rise to human genetic disease (19). It is striking that many mutations appear to exclusively affect the C-terminus of MeCP2, to which no biochemical function has yet been attributed. We clearly have much still to learn about this protein.
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Besides Rett syndrome, mutations in MECP2 are now thought to contribute to some cases of non-specific X-linked mental retardation (20) and Angelman syndrome (21). As Rett syndrome patients have some autistic features, autism patients have also been screened for MECP2 mutations, with no MECP2 mutations found (22). Another study found MeCP2 mutation in two autistic patients who meet Rett syndrome preserved speech variant criteria (23). In the latest study only two of 69 autism patients were shown to have de novo MECP2 mutations (24). At present, the significance of MECP2 mutations in X-linked mental retardation, Angelman syndrome and autism is not clear because of low mutation frequency and relatively wide variability of Rett syndrome symptoms.
Rett syndrome is almost exclusively a disease of females because MECP2 is X-linked and patients are heterozygous for the mutated allele. Following random X chromosome inactivation, typically half of their cells express wild-type (wt) MECP2 and the other half express the mutated MECP2. As a result, the female cell population is mosaic for expression of the mutant allele. This mixture of functionally MECP2+ and MECP2- cells leads to Rett syndrome. Symptom-free female carriers of such MECP2 mutations have only been seen in very rare cases where extreme skewing of X chromosome inactivation prevents expression of the mutated allele (25).
Males that are hemizygous for comparable MECP2 mutations rarely live beyond 2 years and have a different and more severe phenotype than Rett syndrome, usually involving congenital encephalopathy (25,26). There are, however, very rare males with classical Rett syndrome (27). In these individuals, an MECP2 mutation appears to have arisen early in development, giving rise to clones of mutant and wt cells in the same individual that mimic the mosaic expression of the mutant and wt MECP2 genes in MECP2+/- females.
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MeCP2–METHYL CpG BINDING PROTEIN 2 |
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The original methyl-CpG binding activity known as MeCP1 was reported in crude nuclear extracts through its ability to bind a methylated DNA probe containing multiple methylated CpGs (28). Later, a second activity, MeCP2, was detected as an 80 kDa protein that could bind a single methylated CpG in a south-western assay (29). In mouse cells, MeCP2 is detectable throughout the metaphase chromosome arms, but is concentrated in the pericentromeric heterochromatin, which contains highly methylated satellite DNA (30). The methyl-CpG binding domain (MBD) of MeCP2 was mapped near the N-terminus by construction of deletion mutants (Fig. 1) and DNase I in vitro footprinting indicated that it could protect a 12 nucleotide region surrounding a methyl-CpG site. The approximate dissociation constant was 10-9 M. Symmetrically methylated CpG is required for in vitro binding, whereas hemi-methylated DNA is only weakly bound (31). The search for other MBD-like domains revealed another four proteins, which were assigned to the MBD family—MBD1, MBD2, MBD3 and MBD4 (7).
MeCP2 was suggested to bind methylated CpGs without major impediment from the nucleosome surface (32). This finding is compatible with the structure of an MBD (from MBD1) in complex with DNA, which indicates that access to methyl-CpG sites exposed in the major groove might occur without encountering steric interference from the core histones (33).
Early experiments suggested the MeCP2 was targeted to methyl CpG sites in vivo, as heterochromatic localization was lost in mouse cells lacking the DNA methyltransferase Dnmt1 (30). More directly, several chromatin immunoprecipitation (ChIP) experiments have shown that MeCP2 is bound to methylated DNA in vivo, but does not associate with non-methylated DNA. Examples include the ‘differentially methylated regions’ of the imprinted U2af1-rs1 and H19 genes in mouse, the silenced metallothionein I promoter and sodium channel II promoters in Rat-1 cells, and the methylated p14(ARF)/p16(INK4A) CpG islands in human cancer cells (34–40). These findings support the idea that MeCP2 functions by binding to methyl-CpG sites in vivo. Furthermore, the observations that missense mutations in Rett syndrome patients are highly clustered at the MBD of MeCP2 and cause decreased binding to methylated DNA (41–43) imply that methyl-CpG binding by MeCP2 is essential for brain function.
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MeCP2 AS TRANSCRIPTIONAL REPRESSOR |
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Many genes are silenced when the promoter becomes methylated. Therefore, MeCP2 was initially hypothesized to be a transcriptional repressor. This was confirmed by transient transfection studies which showed that MeCP2 is able to repress transcription both in cells and in vitro (44,45). MeCP2's repression properties were investigated by monitoring reporter gene expression following fusion of the GAL4 DNA binding domain with various parts of the Mecp2 gene (45). An
100 amino acid domain in the middle of the protein was found to be responsible for transcriptional repression (TRD). Tethered MeCP2 was found to repress transcription from up to 2000 bp from the transcription initiation site (45). Immunoprecipitation from HeLa nuclear extracts and partial MeCP2 complex purification from Xenopus laevis oocytes uncovered the mSin3A/HDAC1,2 corepressor complex as an interaction partner for MeCP2 (46,47). Treating cells with the HDAC inhibitor TSA partially relieves MeCP2 mediated repression, supporting HDAC involvement in transcriptional repression. Candidate approaches have since identified several other interacting proteins—including transcription factor TFIIB, the proto oncogene c-ski, the DNA methyltransferase DNMT1 and histone methyltransferase Suv39H1 (35,38,48–50). The lack of clear target genes as an in vivo assay for MeCP2 function has made it difficult to draw firm conclusions about the importance of these interactions, although there is evidence that the association of MeCP2 with Suv39H1 contributes to H19 silencing in mouse cells (35). The balance of evidence therefore suggests that MeCP2 can act as a transcriptional repressor in vivo. Whether this function has relevance to Rett syndrome now depends on progress in identification of bona fide target genes in the brain (see below).
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THE Mecp2-NULL MOUSE |
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The first attempt to make Mecp2-null mice by insertion mutation of a promoterless lacZ/neomycin cassette into Mecp2 locus was unsuccessful (51). Chimeric embryos with a high proportion of mutant ES cells had developmental defects and died in mid-gestation. Mecp2-null mice were, however, produced subsequently using cre/lox recombination technology (52,53). The discrepancy between these two sets of results could be explained if MeCP2-deficiency during in vitro culturing of mouse ES cell lines reduces their pluripotency, but this has yet to be tested. Mecp2-null male (Mecp2-/y) and female (Mecp2-/-) mice generated via cre/lox recombination have no apparent phenotype until around 6 weeks. There follows a period of rapid regression resulting in reduced spontaneous movement, clumsy gait, irregular breathing, hindlimb clasping and tremors. Rapid progression of symptoms leads to death at
8 weeks of age (52,53). Detailed brain examination revealed reduced brain and neuron cell size (53). Conditional deletion of Mecp2 in brain only was achieved by crossing mice with intronic loxP sites flanking Mecp2 to mice expressing cre under the nestin promoter. Nestin is expressed mainly in neuronal progenitors from around embryonic day 12 (54). Mice with nestin–cre mediated Mecp2 deletion showed the same phenotype as Mecp2-null mice (52,53). This finding led to two important conclusions: (a) the Mecp2 mutation in the brain is sufficient to produce the same phenotype as a ‘whole animal’ nulls; (b) the presence of wt MeCP2 protein until embryonic day 12 is not enough to rescue or even relieve the phenotype. Deletion of Mecp2 in postmitotic neurons (i.e. still later in brain development) using the CamKII promoter to drive cre recombinase (55) led to delayed onset of symptoms by up to 3 months (Fig. 2) (53). Interestingly the time between deletion of the gene and manifestation of symptoms remained approximately the same (60 days).
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Mecp2+/- FEMALES—A MOUSE MODEL FOR RETT SYNDROME? |
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Numerous Rett syndrome studies failed to find a strong correlation between the location of different MECP2 mutations and severity of the disease. Some report that truncations are more severe than point mutations, but others do not observe this (26,56–60). The absence of a strong correlation between mutation type/location and symptoms suggests that Rett syndrome may be caused by loss of MeCP2 function regardless of the precise mutation involved. If so, the appropriate genetic mouse model for Rett syndrome may be a female mouse heterozygous for the Mecp2-null allele. These heterozygous mice are normal until they are around 9 months old, when they start showing breathing irregularities and hand limb clasping. Reduced mobility was confirmed by an open field test (52). There is a striking parallel between the time of symptom onset in heterozygous mice and in Rett patients, despite the vast developmental difference between a 1-year-old infant human and a 9-month-old mouse that has already raised several litters.
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TRUNCATING MeCP2 MUTATION IN MICE |
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Around 80% of all Rett-causing mutations lie in characterized functional domains of MeCP2: the MBD and the TRD. Currently no function has been mapped to the C-terminus, but mutations which disrupt C-terminus in humans cause Rett syndrome. Mice with C-terminally truncated MeCP2 revealed some interesting findings. The symptom onset window in hemizygous mutants was increased from slight tremors at 6 weeks to kyphosis, visible tremors and seizures at around 5 months of age (61). Thus, in mice, the C-terminal deletion of Mecp2 shows a significantly less severe phenotype than the null mutation (61). The difference between null mutation and C-terminal truncation also suggests that mice, in contrast to humans, may show a clear genotype–phenotype correlation for Mecp2 mutations affecting different regions of the protein.
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MeCP2 EXPRESSION IN BRAIN |
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Expression of MeCP2 is ubiquitous in mouse rat and humans, although levels vary widely between tissues. In brain, MeCP2 is preferentially expressed in neurons but not in glia. Laser scanning cytometry revealed an increase in the number of high MeCP2 expressing neurons at postnatal development in humans, and this expression correlated with alternative polyadenylation (62). In situ hybridization in mouse and rat brains also showed MeCP2 up-regulation postnatally (63–65). MeCP2 expression studies in olfactory epithelium, which contains both mature and immature olfactory receptor neurons, demonstrated that only mature olfactory receptor neurons up-regulate MeCP2 before synaptogenesis (66). Does MeCP2 bind methylated CpG in the brain? In situ hybridization to mouse brain slices suggested that MeCP2 is concentrated within DAPI bright spots of mouse neurons (67). More detailed compartmentalization studies showed co-localization of 5-methylcytosine as well as the major-satellite DNA with MeCP2 in large neurons (68).
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THE SEARCH FOR MeCP2-REGULATED GENES |
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A microarray approach was used in search of transcriptional consequences of MeCP2 loss in mouse brain (69). Surprisingly the experiments showed no major changes in the transcriptome, although some gene expression variation was noticed. Statistical analysis, based on gene expression variability, could, however, distinguish Mecp2-null from wt brains. Some of the genes were confirmed to show small (up to 35%) differences by an RNase protection assay (69). One interpretation could be that brain is a very heterogeneous tissue, making it difficult to detect regional transcription differences due to MeCP2 loss. Alternatively, limitations to the sensitivity of microarray technology may prevent the accurate detection of low abundance transcripts and of small, but perhaps significant, changes in transcription (70). Another possible interpretation of this result is that MeCP2 has a transcription-independent role in the brain.
Recent progress in identifying MeCP2 target genes has relied on a candidate gene approach. Stancheva et al. (71) used Xenopus laevis as a model organism, taking advantage of antisense morpholino oligonucleotide injection to knock-out gene expression. MeCP2-deficient frog embryos had multiple developmental abnormalities in the head and dorsal axis. Developmental defects, together with the MeCP2 expression pattern suggested that lack of MeCP2 caused a problem in neurogenesis. The possibility of a gene mis-expression was therefore explored by investigating candidate genes in the Delta/Notch signalling pathway, which is known as a key pathway in early neuronal development. The Hairy2a gene was found to be up-regulated in MeCP2-deficient frog embryos. Further experiments showed that the Hairy2a promoter has methylated CpGs nearby with MeCP2 bound to them. Repression of the Hairy2a promoter depends on the MeCP2 interaction with SMRT complex via Sin3A. After Notch-mediated induction of Hairy2a, MeCP2 leaves the methylated CpGs, together with Sin3A, histone deacetylase and the SMRT complex. Thus Xenopus Hairy2a provides the first documented case of a gene that is normally repressed by MeCP2 (Fig. 3).
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METHYL-CpG BINDING PROTEINS AND THE BRAIN |
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Recent data has highlighted that neurological defects occur when methyl-CpG binding proteins are mutated or deleted in mouse models. Mbd2-null females neglect their offspring, probably due to an unknown neurological lesion (72). Also, Mbd1-null mice show reduced neuronal differentiation and chromosome instability in vitro and the mice have defective spatial learning and long-term potentiation in hippocampus (73). As described earlier, Mecp2-null mice have more severe neurological symptoms and die at around 8 weeks of age (52,53). As MBD proteins share methyl-CpG binding domain, these findings raise the question: what role does DNA methylation play in the brain? Removing Dnmt1, the maintenance DNA methyltransferase, has a very severe phenotype resulting in failure of mouse embryo development (74), but post-natal deletion of Dnmt1 in neurons does not affect animal viability, as might be expected in non-dividing cells (75). Tissue specific removal of Dnmt1 in mouse central nervous system precursors using nestin–cre mediated deletion, however, led to absence of viable offspring, although embryos were recovered at all stages (75). After a Caesarean section, death occurred within 1 h due to respiratory failure. Occasional gasping was seen, but there was no rhythmic breathing. Interestingly both Mecp2-null mice and Rett patients show breathing abnormalities.
Functions for MBD proteins outside of the brain have recently been described. Helper T cell differentiation is abnormal in MBD2 null mice due to faulty silencing of the Il4 gene both before and during differentiation (76). It may be significant that the deregulation of Il4 expression was only revealed when individual cells were assayed by cell sorting experiments. Changes of this magnitude could be easily missed by global gene expression analysis tools, such as those used to study gene expression changes in the Mecp2-null mouse brain.
A study by Guan et al. (77) demonstrated an intriguing link between different neurotransmitters and the chromatin state of the C/EBP promoter in the mollusc Aplysia. Treating the synapse with the facilitatory transmitter 5-HT recruited CREB1 with CBP histone acetylase, which causes histone acetylation and expression of the gene. On the other hand, treatment with inhibitory transmitter FMRFa brought CREB2 repressor with HDAC5 to the C/EBP promoter, leading to deacetylation of chromatin and silencing of the gene (77). As there is a close interplay between the chromatin modifications and DNA methylation, it is likely that silencing of certain neuronal genes relies on DNA methylation and recruitment of MeCP2, as already indicated for the Hairy2a gene in frog embryos (71) (Fig. 3). It has also been proposed that the extensive DNA replication-independent replacement of histone H3 in neurons may rely on MeCP2 to re-establish appropriate histone modifications (78). The study of chromatin structure in the brain is in its infancy, but we can look forward to rapid developments as we unravel the pathways that involve MeCP2 in neurological development and, with them, the reasons why MeCP2-loss leads to Rett syndrome.
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ACKNOWLEDGEMENTS |
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We thank Helle Jørgensen, Rob Klose and Jacky Guy for critical reading and discussions, and Dr Alison Kerr (Glasgow University) for advice. S.K. holds a studentship from the Darwin Trust (Edinburgh). This work was supported by the Wellcome Trust.
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FOOTNOTES |
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* To whom correspondence should be addressed. Tel: +44 1316505670; Fax: +44 1316505379; E-mail: a.bird{at}ed.ac.uk
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