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CpG Islands and DNAMethylationFrancisco Antequera, CSIC/Universidad de Salamanca, Salamanca, Spain

Methylated CpG dinucleotides at position 5 of cytosine are associated with

transcriptional repression and an inactive chromatin conformation in mammals. CpG

islands arenonmethylated,CpG-rich regionsof �1 kb that represent approximately 1%

of the genome and contain promoters and deoxyribonucleic acid (DNA) replication

origins.

Introduction

Cytosine methylated at position 5 of its pyrimidine ring isfound inmany eukaryotic genomes. In animals, the amountand localization of 5-methyl-cytosine (5-mC) varies widely.It ranges from undetectable levels in the nematodeCaenorhabditis elegans tomosaic methylation affecting onlysome deoxyribonucleic acid (DNA) regions, such as in somecnidarians, molluscs and echinoderms. Vertebrates repre-sent the groupof animalswithhighest level ofgenomicDNAmethylation and 5-mC spreads throughout almost their en-tire genome. Because methylated cytosines are always fol-lowed by a guanine,methylation is often referred to in termsof methylated or nonmethylated CpG dinucleotides.Methylation is symmetrically organized on the DNA dou-ble helix, whichmeans that amethylatedCpG ismatched byanother methylated CpG in the complementary strand(Figure1).Approximately 80%ofallCpGs in the genomearemethylated in mammals, allowing the existence of a poten-tially huge number of different methylation patterns. Theinformation contained in these patterns can be changedwithout altering thenucleotide sequence, and it is inheritableacross cell divisions though a maintenance mechanism thatmethylates CpGs in the daughter strand during DNA rep-lication onlywhen they are complementary toCpGs alreadymethylated in the parental strand. The genome expansionthat accompanied the emergence of vertebrates probablyallowed the acquisition of new functions but, at the sametime, generated the problem of managing a very largeamount of DNA where only a minority of sequences wererelevant for its correct regulation.The following sectionswilldiscuss how this potential conflict could have been attenu-ated by the parallel expansion of DNAmethylation and theemergenceof two families of specializedproteins responsiblefor the establishment and maintenance of the methylationpatterns and for interpreting the information they encoded.

Organization of 5-methyl-cytosine andCpG Islands in the MammalianGenome

Methylated and nonmethylated CpGs are not randomlyinterspersed in the genome but, instead, they are segregated

in two very different compartments. Approximately halfof all nonmethylated CpGs are clustered in regions about1-kb long, known as CpG islands. In humans, there areabout 25 000 CpG islands that altogether represent 1% ofthe genome. In addition to their lack of methylation, CpGislands have an average G+C content of 65% and an av-erage frequency of one CpG per 10 bp. The G+C contentof the rest of the genome is 41%and theobserved frequencyof CpG dinucleotides (one CpG per 100 bp, approxi-mately) is only 20% of that expected. This is because spon-taneous deamination of 5-mC generates thymine, whichhas led to the replacement of a significant amount of meth-ylated CpGs by TpGs (or CpAs in the complementarystrand) along evolution. The 10-fold difference in CpGdensity between nonisland DNA and the CpG islandsreadily allows their identification by plotting the distribu-tion of CpGs across specific genomic regions (Figure 2).Based on this property and on their high G+C content,several algorithms have been developed for the computa-tional identification ofCpG islands in the human and othermammalian genomes. Their predictions, however, varywidely, since the final estimates are very sensitive to smallvariations in the parameters used to define the size, CpGfrequency, and base composition of the CpG islands(see references in Hackenberg et al., 2006). See also: CpGDinucleotides and Human Disorders; DNA Methylationand Mutation; Mutations in Human Genetic Disease;Nucleotide Substitution: Rate ofEarly studies by Tazi and Bird revealed that the chro-

matin organization of CpG islands in the cell nucleus haddistinctive properties as regards the bulk of the genome interms of accessibility to nucleases and in having highlyacetylated histones H3 and H4 (Figure 3 and see FurtherReading). Recent genome-wide approaches involvingchromatin immunoprecipitation with antibodies againsthistonemodifications coupled withDNAmicroarray anal-yses have confirmed and extended these observations byshowing that histone H3 present in CpG islands has a highlevel of methylated lysine 4 (Weber et al., 2007) and ace-tylated lysines 9 and 14 (Roh et al., 2005), which in somecases peaks at the transcription initiation region. Veryoften, this region colocalizes with a nucleosome-free gap

Article Contents

Advanced article

. Introduction

. Organization of 5-methyl-cytosine and CpG Islands in the

Mammalian Genome

. Origin and Maintenance of Methylation Patterns during

Development

. Mammalian DNA-methyltransferases

. Proteins that Interpret the Methylation Signal

. Functions of DNA Methylation in Mammals

doi: 10.1002/9780470015902.a0005027.pub2

ENCYCLOPEDIA OF LIFE SCIENCES & 2007, John Wiley & Sons, Ltd. www.els.net 1

hypersensitive to DNAase I. These properties, togetherwith the absence of proteins that bind methylated CpGs(see later), confer CpG islands with properties typical ofwhat is operationally defined as ‘open’ or ‘active’ chroma-tin. See also: Chromatin Structure and Domains; DNAMethylation and Histone Acetylation

An essential feature of CpG islands is their associationwith the promoter region of almost 70% of all humangenes. This includes most housekeeping genes and

approximately half of the genes with a tissue-restricted ex-pression pattern (Antequera, 2003). In most cases, CpGislands remain nonmethylated throughout developmentregardless of the expression of the associated genes. Thisraises the question of how they manage to maintain theirnonmethylated status in an otherwise heavily methylatedgenome. CpG island sequences are not intrinsically refrac-tory to methylation, as illustrated by the methylation ofsome of them in vivo in certain particular cases (see later).Given their enhanced accessibility to nucleases in the nu-cleus, a passive mechanism through which they might beinaccessible to DNA methyltransferases seems unlikely.An alternative mechanism could involve a DNA de-methylase activity specific for CpG islands to remove ac-cidentallymethylatedCpGs, although the existence of suchactivity has not been confirmed unequivocally. It is alsopossible that the biased base composition of CpG islandsmight have arisen along evolution as a consequence of ahigher rate of damage and repair due to their dual activityas promoters andDNAreplication origins. In keepingwiththis possibility, it has been found that the large majority ofgenes expressed very early on during development are as-sociated with CpG islands (Ponger et al., 2001). See also:DNADemethylation; DNAMethylation inDevelopment;Promoters: Evolution

Origin and Maintenance ofMethylation Patterns duringDevelopment

As discussed earlier, most CpG islands remain nonmeth-ylated, regardless of the expression of their associatedgenes. Notable exceptions to this general situation aremanyCpG islands in the inactiveX chromosome and thoseassociated with genes subject to genomic imprinting (Reikand Lewis, 2005). In all cells of mammalian females, one ofthe two X chromosomes is inactivated early during devel-opment to compensate for the genetic-dosage differencesrelative to males, which only have one X chromosome in-herited from their mothers. Except for the �15% of genesthat escape inactivation, the vast majority of CpG islandsin the inactive X chromosome are fully methylated andadopt an inactive chromatin conformation that is associ-ated with the transcriptional shutdown of the associatedgenes. Among animals, genetic imprinting is a phenome-non unique to mammals, and imprinted genes are definedas those whose expression is determined by their parentalorigin. Thismeans that in a diploid cell only the paternal ormaternal copy of an imprinted gene will be expressed, incontrast with the largemajority of genes in the genome thatare expressed from both alleles. In the mouse, �80 im-printed genes have been identified, of which some – but notall – are also imprinted in humans. In most cases charac-terized to date, imprinted genes are organized in clustersthat contain between 3 and 10 protein coding genes and atleast a noncoding ribonucleic acid (RNA). A common

Figure 1 Three-dimensional structure of a double-stranded DNA fragment

containing four methylated CpG dinucleotides. The methyl groups of the

complementary methylated CpGs protrude into the major groove of the

DNA molecule.

CpG Islands and DNA Methylation

ENCYCLOPEDIA OF LIFE SCIENCES & 2007, John Wiley & Sons, Ltd. www.els.net2

feature of these clusters is the presence of a differentiallymethylated region (DMR) that has a CpG density compa-rable to that of CpG islands and shows a parental allele-specific methylation.Methylation of DMRs is essential forimprinting maintenance, as shown by the biallelic expres-sion or repression of imprinted genes in mice where theDNA-methyltransferase genes have been mutated.See also: Genomic Imprinting at the Transcriptional Le-vel; Imprinting: Evolution; Imprinting (Mammals);X-Chromosome Inactivation

Although the global DNA methylation patterns remainstable during development, recent analyses have shownthat a small number of CpG islands are de novomethylatedin somatic tissues in addition to those associated with im-printed genes and in the inactive X chromosome (Weberet al., 2007). This developmentally regulated de novo me-thylation, together with the need to reset the imprintingmarks in the gametes depending on the sex of the organism,implies that methylation patterns must be reset and estab-lished very early on during development.

In mammals, sperm and egg genomes have a global levelof methylation comparable to that of somatic cells. Uponfertilization, however, both the paternal and maternal ge-nomes are demethylated in such away that at the blastocyststage the genome is virtually devoid of methylation. Thedemethylation mechanism, however, is different in bothgenomes. In the case of the paternal genome, demethylat-ion occurs very fast and must involve some active de-methylation mechanism because it takes place in theabsence of DNA replication. The maternal genome is alsodemethylated, although to a lesser extent than the paternal

one, but in this case the process is due to the lack ofmethylation maintenance activity during early cleavagedivisions. Between implantation and gastrulation, a waveof de novomethylation resets the methylation patterns thatwill later be transmitted to the somatic cells making up theentire organism. The specific methylation pattern of thegametes is established by de novo methylation duringgametogenesis. Thus, the interplay of demethylation,de novo, and maintenance methylation erase, re-establishand maintain specific methylation patterns in each gener-ation. See also: DNA Methylation in Development

Mammalian DNA-methyltransferases

The symmetric and postreplicative methylation of CpGsled to the discovery of a DNA-methyltransferase activitycapable of methylating hemimethylated DNA in vitro at arate 5- to 30-fold greater than a fully unmethylated subst-rate and to the subsequent isolation of theDNMT1 gene inmice and humans. Approximately 500 amino acids at theC-terminus of the mouse DNMT1 protein show homologywith bacterial cytosine methyltransferases, while the re-maining 1100 residues at the amino end contain a nuclearlocalization signal and a domain for the association withreplication foci, consistent with its activity of copying themethylation pattern of the parental DNA strands on to thedaughter strands during replication (Goll and Bestor,2005). The essential role of DNA methylation in mamma-lian development was clearly demonstrated by the embry-onic lethal phenotype of mice in which theDnmt1 gene had

α-Globin 500 bp

β-Globin

5-ALAS

ADO

Figure 2 Examples of human genes with and without CpG islands. The diagrams show the distribution of CpGs across the 5’ end of four human genes.

The a-globin and the aldose reductase (ADO) genes are associatedwith CpG islands, as is clearly shown by the high density of CpG dinucleotides around their 5’ends. In contrast, the frequency of CpGs at the 5’ ends of the b-globin and the 5-aminolevulinate synthase 2 (5-ALAS) genes is similar to the genome average.

Vertical lines indicate CpGs. Boxes represent exons and arrows show the transcription initiation site. Only exon 1 of the ADO and 5-ALAS genes is shown.



been inactivated. Surprisingly, embryonic stem (ES) cellsderived from these embryos retained about one-third of thewild-type level of genomic methylation and were proficientat methylating de novo infective retroviral DNA. These EScells, however, died when induced to differentiate, and theywere unable to repress the expression of intracisternal Aparticle (IAP) transposons and long-terminal repeat (LTR)retroposons, which remain silent in normal cells. The per-sistence ofmethylatedDNA in cells devoid ofDnmt1 led tothe identification of the mouse and human DNMT3A andDNMT3B genes, which are expressed at high levels in un-differentiated ES cells and at much lower levels in adultsomatic tissues. The DNMT3A and DNMT3B methylt-ransferases, unlike DNMT1, methylate hemimethylatedand nonmethylated DNA with equal efficiency. Inactiva-tion of both genes in mouse ES cells prevents the de novomethylation of infective retroviral DNA and genomicde novo methylation in post-implantation embryos.Homozygous null mice mutants for the Dnmt3a andDnmt3b genes die during embryogenesis or soon afterbirth. Although these two proteins have partially over-lapping functions in vivo, they play different roles. Forexample, DNMT3B – but not DNMT3A – specificallymethylates the centromericminor satellite repeats inmouseES cells. Mutations in the human DNMT3B gene are as-sociated with the ICF (immunodeficiency, centromere in-stability and facial anomalies) syndrome, and lymphocytesderived from these patients show undermethylation anddecondensation of subcentromeric satellite regions, sug-gesting that mice carrying mutantDnm3b genes could be auseful model for the human ICF syndrome.

The DNMT2 protein is an enigmatic member of theDNA-methyltransferase family. Although it contains the10 domains characteristic of 5-mC methyltransferases andalthough the gene is active in most human and mouse tis-sues, biochemical analyses have failed to detect any meth-yltransferase activity, and homozygous disruption of themouse Dnmt2 gene does not cause any detectable pheno-type or alteration in the DNA methylation patterns (Golland Bestor, 2005).

DNMT3L is structurally related to DNMT3A andDNMT3Bbut lacksDNAmethyltransferase activity and isthought to act as a cofactor of DNMT3A. Dnmt3L is spe-cifically expressed in germ cells and is essential for the es-tablishment of maternal imprinting and for themethylation and silencing of transposons in males. Maleand female Dnmt3L null homozygous mice are viable butsterile. The subtlety and sophistication involved in the es-tablishment of the methylation patterns early on duringdevelopment is further illustrated by the sex-specific usageof 5’ exons in the Dnmt1 gene. Dnmt1o results from theincorporation of an oocyte-specific 5’ exon into the somaticDnmt1 gene. The DNMT1o protein is retained in the cy-toplasm of very early embryos and briefly enters the nucleiat the 8-cell stage. A different 5’ exon that prevents trans-lation of the DNMT1 mRNA is used in pachytene sperm-atocytes. See also:DNAMethylation; DNAMethylation:Enzymology; DNA Methylation: Evolution; Promoters:Evolution

Proteins that Interpret theMethylation Signal

The simplest way for methylation to exert its re-pressive effect on transcription is by directly pre-venting the binding of transcriptional activators to DNA.While in some cases this mechanism can be operative, theemergence of the genome-wide methylation pattern of ver-tebrates was paralleled by the appearance of proteins ca-pable of interpreting the information encoded in themethylation patterns (Klose and Bird, 2006). About 15years ago, Adrian Bird and his collaborators identified twonuclear protein activities, named MeCP1 and MeCP2 (formethyl-CpG-binding proteins), whose only requirementfor binding toDNAwas the presence of methylated CpGs.This property made such activities ideal candidates formediating the indirect repressive effect of methylation ontranscription. See also: Methylated DNA-binding Pro-teins; Methylation-mediated Transcriptional Silencing inTumorigenesisMeCP2 was the first member of the family to be cloned

and its analysis revealed that it consisted of a single poly-peptide containing a methyl-CpG-binding domain (MBD)and a transcriptional repressor domain (TRD) capable ofsilencing transcription even when bound to DNA througha heterologous DNA-binding domain. The TRD domainwas found to interact with the transcriptional co-repressorSIN3A and with histone deacetylases, suggesting a mech-anistic link between transcriptional repression, DNA me-thylation and histone deacetylation. However, despite itshigh levels in postmitotic neurons in mouse brain, inacti-vationof theMeCP2 gene inmice does not result in a globalchange in the pattern of gene expression in the brain but inthe specific upregulation of a few imprinted genes, andsome glucocorticoid- and calcium-inducible genes. An es-sential finding that underscores the relevance ofMeCP2 for

HS

500 bp

Nucleosomes withacetylated histonesNucleosomes withdeacetylated histones

Histone H1

MeCP and MBD protein complexesbinding to methylated CpGs

Figure 3 Schematic representation of the chromatin structure of a CpG

island. Vertical lines indicate CpGs. Most CpGs outside the islands are

methylated (indicated by a black dot), while CpGs within the island remain

nonmethylated. Transcription initiation from a nucleosome-free gap is

indicated with an arrow. HS: sites of hypersensitivity to DNAase; MeCP:

methyl CpG-binding protein; MBD: methyl CpG-binding domain.



normal brain functioning is that several mutations in theMBD and TRD domains of the humanMECP2 gene havebeen identified in patients suffering from Rett’s syndromeand that similar neurological disorders are present inMeCP2-deficient mice.

MeCP1 was the first methyl-CpG-binding activity iden-tified and it was later shown to consist of a complex be-tween the MBD2 protein and the nucleosome remodellingand histone deacetylaseNuRD/Mi-2 complex.MBD2 alsocontains anMBD and an overlapping TRD domain and itrecognizes methylated CpGs dinucleotides. Mbd2-nullmice are fertile and show very specific phenotypes, suchas a behavioural abnormality consisting of the failure tonurture their offspring, a reduced incidence of colon cancerin a genetic background prone to intestinal tumorigenesisand significant alterations in the regulation of cytokineexpression.

A search for proteins containing a MBD motif ho-mologous to that of MeCP2 and MBD2 allowed theidentification of the MBD1, MBD3 and MBD4 proteins.Mbd1 represses transcription through a TRD domain ina methyl-CpG-dependent manner. It is a chromosomalprotein enriched in human hypoacetylated centromericheterochromatin in vivo, and disruption of the mouseMBD1 gene causes mild neurological defects. MBD1forms a complex with the histone H3 lysine 9 (H3K9)methyltransferase SETDB1, which binds to the chroma-tin assembly factor CAF-1 during DNA replication(Sarraf and Stancheva, 2004). This suggests that specificpatterns of DNA and H3K9 methylation could be trans-mitted to the newly replicated genomes by the CAF-1/MBD1/SETDB1 complex. MBD3 is the only member ofthe family that does not bind methylated DNA becausetwo amino acid changes at the MBD domain abolish itsmethyl-CpG-binding activity. Like MBD2, MBD3 is acomponent of the NuRD/Mi-2 complex, and despite thehigh structural similarity between them they are notfunctionally redundant, as shown by the lethal embry-onic phenotype caused by disruption of the Mbd3 genein the mouse. MBD2 and MBD3 are the only membersof the MBD family for which orthologous genes havebeen identified in invertebrates such as Drosophila andCaenorhabditis in which both functions are encoded by asingle gene. Finally, MBD4 has a glycosylase domainthat suggests its involvement in the repair of 5-mCpG/TpG mismatches caused by the spontaneous deamina-tion of 5-mC. This role is strongly supported by itshigher affinity in vitro for 5-mCpG/TpG mismatchesthan for symmetrically methylated CpG dinucleotidesand because of the increase in cytosine-to-thymine tran-sitions in Mbd4-null mice. Further support for its func-tion in reducing the mutational load of methylatedcytosines is that the MBD4 gene is mutated in a highproportion of human colorectal tumours showing mi-crosatellite instability. Recent results have suggested thatin addition to this function the MBD4 protein mightalso be involved in transcriptional repression like theremaining members of the MBD family.

The KAISO protein does not have an MBD domainbut binds methylated CpGs through zinc fingers in itsC-terminus.KAISO is amemberof theBTB/POZ family oftranscription factors and represses transcription by target-ing the histone deacetylase-containing N-CoR complex tospecific CpG-methylated sequences.

Functions of DNA Methylation inMammals

Despite the overwhelming amount of evidence in-dicating that DNA methylation is associated with tran-scriptional repression, the role of DNA methylationas a primary regulator of gene expression remains elusive.With the exceptions mentioned earlier, the large majorityof CpG islands consistently remain nonmethylatedthroughout development regardless of their transcription,and therefore do not qualify as genetic switches for turninggenes on and off. However, it is unclear whether thedemethylation of a fewCpG sites in the promoter region ofsome non-CpG island genes in expressing tissues is a causeor a consequence of their transcriptional activation.On more general grounds, it has been argued that DNAmethylation would be unlikely to play a major role in reg-ulating the genetic networks underlying mammalian de-velopment because networks sharing a similar logicoperate in many invertebrates and other organismswith little or undetectable genomic methylation. See also:DNA Methylation: Evolution; DNA Methylation inDevelopmentTranscriptional repression in heterochromatic regions

in organisms such as Schizosaccharomyces pombe,Drosophila melanogaster or C. elegans is efficiently imple-mented without the benefit of DNA methylationby histone-modifying enzymes that in most cases in-clude H3K9 histone methyltransferases. The H3K9signal is used to recruit heterochromatin proteins such asHP1, which induces the transcriptional silencing of thetargeted regions. A direct relationship between histonemodification and DNA methylation has been reported inNeurospora crassa. This fungus has 1.5%of all its cytosinesmethylated, which makes it one of the few fungi with de-tectable levels of methylated DNA. The dim-5 and hpogenes encode a H3K9 histone methyltransferase and ahomologue of HP1 that binds to nucleosomes bearing theH3K9 modification and acts as an adaptor between H3K9methylated histones and DNA methylation. The func-tional relationship between both epigenetic systems wasdramatically shown by the complete loss of genomicmethylation as a consequence of mutating either thedim-5 or hpo genes. See also: Gene Silencing in Develop-ment (Drosophila)In recent years, a close relationship between DNA me-

thylation and histone modification has also been firmlyestablished in mammals. As discussed earlier, MBD pro-teins play the dual role of recognizing methylated CpGs



and transcriptional co-repressors and chromatin remodel-ling complexes that include histone deacetylases andH3K9histonemethyltransferases.However, there is also evidenceof recruitment of DNMTases by modified histones to me-thylate certain specifically targeted regions. This epigeneticcrosstalk has recently been extended to include the target-ing of the DNA methylation machinery to sites bound byprotein complexes of the Polycomb group (PcG). Theseproteins were originally identified in Drosophila as repres-sors of homeotic genes and were later also found to bepresent in plants and animals. The relationship of PcGproteins with DNA methylation has been recently estab-lished by showing that the PcG protein EZH2 is a histonemethyltransferase that methylates lysine 27 of histone H3or lysine 26 of histone H1. In addition, some specific pro-moters are targeted formethylation through the binding ofEZH2 because of its interaction with the three major hu-man DNA methyltransferases (Vire et al., 2006). See also:Developmental Evolution

This scenario suggests that the genome-wide ex-pansion of DNA methylation (with the exception of theCpG islands) that accompanied the emergence of verte-brates couldhavebeen selected as an additionalmechanismto manage such a large genome. According to this view,DNA methylation could reinforce previously available re-pressive mechanisms to reduce transcriptional noise fromspurious binding sites for transcription factors and frompromoters of transposable elements that represent about45% of the entire human genome. This possibility is con-sistent with the observation that global methylation pat-terns are always present in organisms such as vertebratesand some plants that contain vast amounts of DNA, ofwhich only a small fraction is relevant for coding and reg-ulatory functions. A suggestion that DNA methylation isnot the primary inactivation mechanism is that it is de-ployed at imprinted genes and inactive X chromosomesafter their transcriptional shutdown has been establishedby other means. A more direct role in the silencing oftransposons is suggestedby themassive reactivationof IAPretroviruses in mouse embryos devoid of the maintenanceDNMT1 methyltransferase. This overexpression, how-ever, does not apply to most genes in the genome. It isconceivable that, without neglecting its genome-wide pro-tective function, methylation could have evolved to per-form more specialized tasks unique to mammals, such asX chromosome inactivation and genetic imprinting. Thiswould explain the diversity and specificity of theDNMTases and of the MBD proteins, and the widelydifferent and sometimes subtle phenotypes generated byinactivation of the genes encoding them. See also: DNAMethylation: Evolution

That DNA methylation is essential for mammals is il-lustrated by the lethal phenotypes caused by disruption ofthe genes encoding theDNAmethyltransferases.Whateverthe advantages, however, there is a price to pay for having aheavily methylated genome. Almost one-third of geneticdiseases due to point mutations are caused by the replace-ment of cytosine by thymine due to the spontaneous

deamination of 5-mC. In addition, aberrantmethylation ofCpG islands has a high incidence in tumours and is one ofthe best characterized epigenetic alterations associatedwith gene silencing in cancer cells. See also: ChromatinStructure and Modification: Defects; CpG Dinucleotidesand Human Disorders; DNA Methylation and Mutation;Imprinting Disorders; Methylation-mediated Transcrip-tional Silencing in Tumorigenesis

References

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Further Reading

AntequeraFandBirdA (1999)CpG islands as genomic footprints

of promoters that are associated with replication origins. Cur-

rent Biology 9: R661–R667.

Bernstein BE,Meissner A and Lander ES (2007) The mammalian

epigenome. Cell 128: 669–681.

Bird A (1986) CpG-rich islands and the function of DNA me-

thylation. Nature 321: 209–213.

Freitag M, Hickey PC, Khlafallah TK, Read ND and Selker EU

(2004) HP1 is essential for DNA methylation in Neurospora.

Molecular Cell 13: 427–434.



Hendrich B and Tweedie S (2003) The methyl-CpG binding

domain and the evolving role of DNA methylation in animals.

Trends in Genetics 19: 269–277.

Jones PA and Baylin SB (2007) The epigenomics of cancer. Cell

128: 683–692.

Okano M, Bell DW, Haber DA and Li E (1999) DNA

methyltransferasesDnmt3a andDnmt3b are essential for de novo

methylation and mammalian development. Cell 99: 247–257.

Rollins RA, Haghighi F, Edwards JR et al. (2006) Large-scale

structure of genomic methylation patterns. Genome Research

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Surani MA, Hayashi K and Hajkova P (2007) Genetic

and epigenetic regulators of pluripotency. Cell 128:

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Tazi J and Bird A (1990) Alternative chromatin structure at CpG

islands. Cell 60: 909–920.



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