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CpG Islands

  • Chapter
DNA Methylation

Part of the book series: EXS ((EXS,volume 64))

Abstract

DNA methylation is a conspicuous feature of vertebrate genomes. Approximately 4% of total cytosines are methylated, representing about 5 × 107 5-methylcytosine (5-mC) residues per diploid nucleus. All 5-mC is present in the dinucleotide CpG, although only 70 to 80% of the potentially methylatable sites are actually in a methylated form. Most studies on the relative distribution of methylated cytosines in DNA have relied on the ability of some restriction enzymes to distinguish between the methylated and unmethylated version of the same sequence. This approach has provided information about the methylation patterns at specific genes in different tissues during development and has revealed that the vertebrate genome can be divided into two distinct compartments: the CpG island fraction, representing 1 to 2% of the total genome and containing all the sites that are consistently nonmethylated at all stages of development; and the remaining 98% containing all methylated sites.

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References

  • Abe, K., Wei, J., Wei, F., Hsu, Y., Ueara, H., Artzt, K., and Bennett, D. (1988) Searching for coding sequences in the mammalian genome: The H-2K region of the mouse MHC is replete with genes expressed in embryos. EMBO J. 7, 3441–3449.

    PubMed  CAS  Google Scholar 

  • Antequera, F., Tamame, M., Villanueva, J., and Santos, T. (1984) DNA methylation in the fungi. J. Biol. Chem. 259, 8033 –8036.

    PubMed  CAS  Google Scholar 

  • Antequera, F., and Bird, A. (1988) Unmethylated CpG islands associated with genes in higher plant DNA. EMBO J. 7, 2295–2299.

    PubMed  CAS  Google Scholar 

  • Antequera, F., Macleod, D., and Bird, A. (1989) Specific protection of methylated CpGs in mammalian nuclei. Cell 58, 509–517.

    Article  PubMed  CAS  Google Scholar 

  • Antequera, F., Boyes, J., and Bird, A. (1990) High levels of de novo methylation and altered chromatin structure at CpG islands in cell lines. Cell 62, 503–514.

    Article  PubMed  CAS  Google Scholar 

  • Bell, M., et al. (1991) Physical mapping across the fragile X: hypermethylation and clinical expression of the fragile X syndrome. Cell 64, 861–866.

    Article  PubMed  CAS  Google Scholar 

  • Bickmore, W., and Bird, A. (1992) The use of restriction endonucleases to detect and isolate genes from mammalian cells. Meth. Enzymol. 276, 224–244.

    Article  Google Scholar 

  • Bird, A. (1980) DNA methylation and the frequency of CpG in animal DNA. Nucl. Acids Res. 8, 1499–1504.

    Article  CAS  Google Scholar 

  • Bird, A. (1986) CpG-rich islands and the function of DNA methylation. Nature 321, 209–213.

    Article  PubMed  CAS  Google Scholar 

  • Bird, A. (1987) CpG islands as gene markers in the vertebrate nucleus. Trends Genet. 3, 342–347.

    Article  CAS  Google Scholar 

  • Bird, A., and Taggart, M. (1980) Variable patterns of DNA and rDNA methylation in animals. Nucl. Acids Res. 8, 1485–1497.

    Article  PubMed  CAS  Google Scholar 

  • Bird, A., Taggart, M., and Smith, B. (1979) Methylated and unmethylated DNA compart-ments in the sea urchin genome. Cell 77, 889–901.

    Article  Google Scholar 

  • Bird, A., Taggart, M., Frommer, M., Miller, O., and Macleod, D. (1985) A fraction of the mouse genome that is derived from islands of nonmethylated, CpG-rich DNA. Cell 40, 91–99.

    Article  PubMed  CAS  Google Scholar 

  • Bird, A., Taggart, M., Nichols, D., and Higgs, D. (1987) Non-methylated CpG-rich islands at the human alpha-globin locus: implications for evolution of the alpha-globin pseudogene. EMBO J. 6, 999–1004.

    PubMed  CAS  Google Scholar 

  • Bonneta, L., Kuehn, S., Huang, A., Law, D., Kalikin, L., Koi, M., Reeve, A., Brownstein, B., Yeger, H., Williams, B., and Feinberg, A. (1990) Wilms tumor locus on 1 lpl3 defined by multiple CpG island-associated transcripts. Science 250; 994–997.

    Article  Google Scholar 

  • Brown, W., and Bird, A. (1986) Long-range restriction site mapping of mammalian genomic DNA. Nature 322, 477–481.

    Article  PubMed  CAS  Google Scholar 

  • Brown, T., and Jiricny, J. (1987) A specific mismatch repair event protects mammalian cells from loss of 5-methylcytosine. Cell 50, 945–950.

    Article  PubMed  CAS  Google Scholar 

  • Burmeister, M., Monaco, A., Gillard, E., van Ommen, G., Affara, N., Fergusen-Smith, M., Kunkel, L., and Lehrach, H. (1988) A 10 megabase physical map of human Xp21, including the Duschene muscular dystrophy gene. Genomics 2, 189–202.

    Article  PubMed  CAS  Google Scholar 

  • Carrotti, D., Palitti, F., Lavia, P., and Strom, R. (1989) In vitro methylation of CpG islands. Nucl. Acids Res. 77, 9219–9229.

    Article  Google Scholar 

  • Cooper, D., Taggart, M., and Bird, A. (1983) Unmethylated domains in vertebrate DNA. Nucl. Acids Res. 77, 647–658.

    Article  Google Scholar 

  • Cross, S., Kovarik, P., Schmidke, J., and Bird, A. (1991) Non-methylated islands in fish genomes are GC-poor. Nucl. Acids Res. 79, 1469–1474.

    Article  Google Scholar 

  • De Bustros, A., Nelkin, B., Silverman, A., Ehrlich, G., Poiesz, B., and Baylin, S. (1988) The short arm of chromosome 11 is a “hot spot” for hypermethylation in human neoplasia. Proc. Natl. Acad. Sci. USA 85, 5693–5697.

    Article  PubMed  Google Scholar 

  • Dynan, W. (1986) Promoters of housekeeping genes. Trends Genet. 2, 196–197.

    Article  CAS  Google Scholar 

  • Elgin, S. (1990) Chromatin structure and gene activity. Curr. Opin. Cell Biol. 2, 437–445.

    Article  PubMed  CAS  Google Scholar 

  • Frank, D., Keshet, I., Shani, M., Levine, A., Razin, A., and Cedar, H. (1991) Demethylation CpG islands in embryonic cells. Nature351, 239–241.

    Article  PubMed  CAS  Google Scholar 

  • Goodfellow, P., Mondello, C., Darling, S., Pym, B., Little, P., and Goodfellow, P. (1988) Absence of methylation of a CpG-rich region at the 5’ end of the MIC2 gene on the active X, the inactive X, and the Y chromosome. Proc. Natl. Acad. Sci. USA 85, 5605–5609.

    Article  PubMed  CAS  Google Scholar 

  • Greger, V., Passarge, E., Hopping, W., Messmer, E., and Horsthemke, B. (1989) Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma. Hum. Genet. 83, 155–158.

    Article  PubMed  CAS  Google Scholar 

  • Hansen, R., Ellis, N., and Gartler, S. (1988) Demethylation of specific sites in the 5’ region of the inactive X-linked human phosphoglycerate kinase gene correlates with the appear-ance of nuclease sensitivity and gene expression. Mol. Cell. Biol. 8, 4692–4699.

    PubMed  CAS  Google Scholar 

  • Heitz, D. et al. (1991) Isolation of sequences that span the fragile X and identification of a fragile X-related CpG island. Science 251, 1263–1239.

    Article  Google Scholar 

  • Holliday, R. (1987) The inheritance of epigenetic defects. Science 238, 163–170.

    Article  PubMed  CAS  Google Scholar 

  • Huxley, C., and Fried, M. (1990) The mouse Surfeit locus contains a cluster of six genes associated with four CpG-rich islands in 32 kilobases of genomic DNA. Mol. Cell. Biol. 10, 605–614.

    PubMed  CAS  Google Scholar 

  • Jahner, D., and Jaenisch, R. (1984) DNA methylation in early mammalian development, in: DNA methylation. Biochemistry and biological significance, pp. 189–219. Eds A. Razin, H. Cedar, and A. Riggs. Springer-Verlag, Heidelberg/Berlin.

    Google Scholar 

  • Jones, P., Wolkowicz, M., Rideout, W., Gonzales, F., Marziasz, C., Coetzee, G., and Tapscott, S. (1990) De novo methylation of the MyoDl CpG island during the establishment of immortal cell lines. Proc. Natl. Acad. Sci. USA, 87, 6117–6121.

    Article  PubMed  CAS  Google Scholar 

  • Kaslow, D., and Migeon, B. (1987) DNA methylation stabilizes X chromosome inactivation in eutherians but not in marsupials: evidence for multistep maintenance of mammalian X dosage compensation. Proc. Natl. Acad. Sci. USA 84, 6210–6214.

    Article  PubMed  CAS  Google Scholar 

  • Kolsto, A., Kollias, G., Giguere, V., Isobe, K., Prydz, H., and Grosveld, F. (1986) The maintenance of methylation-free islands in transgenic mice. Nucl. Acids Res. 14, 9667–9678.

    PubMed  CAS  Google Scholar 

  • Kratzer, P., Chapman, V., Lambert, H., Evans, R., and Liskay, R. (1983) Differences in the DNA of the inactive X chromosomes of fetal and extra embryonic tissues of mice. Cell 33, 37–42.

    Article  PubMed  CAS  Google Scholar 

  • Kremer, E. et al. (1991) Mapping of instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science 252, 1711–1714.

    Article  PubMed  CAS  Google Scholar 

  • Lennard, A., and Fried, M. (1991) The bidirectional promoter of the divergently transcribed mouse Surf-1 and Surf-2 genes. Mol. Cell. Biol. 11, 1282–1294.

    Google Scholar 

  • Lewis, J., Meehan, R., Henzel, W., Maurer-Fogey, I., Jeppesen, P., Klein, F., and Bird, A. (1992) Purification, sequence and cellular localisation of a novel chromosomal protein that binds to methylated DNA. Cell 69, 905–914.

    Article  PubMed  CAS  Google Scholar 

  • Lindahl, T. (1982) DNA repair enzymes. Annu. Rev. Biochem. 51, 67–87.

    Article  Google Scholar 

  • Lindsay, S., and Bird, A. (1987) Use of restriction enzymes to detect potential gene sequences in mammalian DNA. Nature 327, 336–338.

    Article  PubMed  CAS  Google Scholar 

  • Lock, L., Takagi, N., and Martin, G. (1987) Methylation of the HPRT gene on the inactive X occurs after chromosome inactivation. Cell 48, 39–46.

    Article  PubMed  CAS  Google Scholar 

  • Mandel, J., and Chambon, P. (1979) DNA methylation: organ specific variations in the methylation pattern within and around ovalbumin and other chicken genes. Nucl. Acids Res. 7, 2081–2103.

    Article  PubMed  CAS  Google Scholar 

  • McClelland, M., and Ivarie, R. (1982) Asymmetrical distribution of CpG in an “average” mammalian gene. Nucl. Acids Res. 10, 7865–7877.

    Article  PubMed  CAS  Google Scholar 

  • McKeon, C., Ohkubo, H., Pastan, I., and Crombrugghe, B. (1982) Unusual methylation pattern of the alpha-2(I) collagen. Cell 29, 203–210.

    Article  PubMed  CAS  Google Scholar 

  • Meehan, R., Lewis, J., McKay, S., Kleiner, E., and Bird, A. (1989) Identification of a mammalian protein that binds specifically to DNA containing methylated CpGs. Cell 58, 499–507.

    Article  PubMed  CAS  Google Scholar 

  • Melton, D., McEwan, C., and McKie, A. (1986) Expression of the mouse HPRT gene: Deletional analysis of the promoter region of an X-chromosome linked housekeeping gene. Cell 44, 319–328.

    Article  PubMed  CAS  Google Scholar 

  • Mohandas, T., Sparkes, R., and Shapiro, L. (1981) Reactivation of an inactive human X chromosome: Evidence for X inactivation by DNA methylation. Science 211, 393–396.

    Article  PubMed  CAS  Google Scholar 

  • Naveh-Many, T., and Cedar, H. (1981) Active gene sequences are undermethylated. Proc. Natl. Acad. Sci. USA 78, 4246–4250.

    Article  PubMed  CAS  Google Scholar 

  • Nicke, H., Bowen, B., Ferl, R., and Gilbert, W. (1986) Detection of cytosine methylation in the maize alcohol dehydrogenase gene by genomic sequence. Nature 319, 243–246.

    Article  Google Scholar 

  • Pfeifer, G., Tanguay, R., Steigerwald, S., and Riggs, A. (1990) In vivo footprint and methylation analysis by PCR-aided genomic sequencing: Comparison of active and inactive X chromosomal DNA at the CpG island and promoter of human PGK-1. Genes Devel. 4, 1277–1287.

    Article  PubMed  CAS  Google Scholar 

  • Pfeifer, G., and Riggs, A. (1991) Chromatin differences between active and inactive X chromosomes revealed by genomic footprinting of permeabilized cells using DNase I and ligation-mediated PCR. Genes Devel. 5, 1102–1113.

    Article  PubMed  CAS  Google Scholar 

  • Pieretti, M., Zhang, F., Fu, Y., Warren, S., Oostra, B., Caskey, C. T., and Nelson, D. (1991) Absence of expression of the FMR1 gene in fragile X syndrome. Cell 66, 817–822.

    Article  PubMed  CAS  Google Scholar 

  • Pugh, B., and Tjian, R. (1991) Transcription from a TATA-less promoter requires a multisubunit TFIID complex. Genes Devel. 5, 1935–1945.

    Article  PubMed  CAS  Google Scholar 

  • Razin, A., and Cedar, H. (1977) Distribution of 5-methylcytosine in chromatin. Proc. Natl. Acad. Sci. USA 74, 2725–2728.

    Article  PubMed  CAS  Google Scholar 

  • Razin, A., Szyf, M., Kafri, T., Roll, M., Giloh, H., Scarpa, S., Carotti, D., and Cantoni, G. (1986) Replacement of 5-methylcytosine: A possible mechanism for transient DNA demethylation during differentiation. Proc. Natl. Acad. Sci. USA 83, 2827–2831.

    Article  PubMed  CAS  Google Scholar 

  • Sakai, T., Toguchida, J., Ohtani, N., Yandell, D., Rapaport, J., and Dryja, T. (1991) Allele-specific hypermethylation of the retinoblastoma tumor suppressor gene. Am. J. Hum. Genet. 48, 880–888.

    PubMed  CAS  Google Scholar 

  • Sharp, P. (1992) TATA-binding protein is a classless factor. Cell 68, 819–821.

    Article  PubMed  CAS  Google Scholar 

  • Shemer, R., Walsh, A., Eisenberg, S., Breslow, J., and Razin, A. (1990) Tissue-specific methylation patterns and expression of the human apolipoprotein A1 gene. J. Biol. Chem. 265, 1010–1015.

    PubMed  CAS  Google Scholar 

  • Somma, P., Pisano, C., and Lavia, P. (1991a) The housekeeping promoter from the mouse CpG island HTF9 contains multiple protein-binding elements that are functionally redun-dant. Nucl. Acids Res. 19, 2817–2824.

    Article  PubMed  CAS  Google Scholar 

  • Somma, P., Gambino, I., and Lavia, P. (1991b) Transcription factors binding to the mouse HTF9 housekeeping promoter differ between cell types. Nucl. Acids Res. 19, 4451–4458.

    Article  PubMed  CAS  Google Scholar 

  • Stein, R., Razin, A., and Cedar, H. (1982) In vitro methylation of the hamster adenine phosphoribosyltransferase gene inhibits its expression in mouse L cells. Proc. Natl. Acad. Sci. USA 79, 3418–3422.

    Article  PubMed  CAS  Google Scholar 

  • Stein, R., Sciaky-Gallili, N., Razin, A., and Cedar, H. (1983) Pattern of methylation of two genes coding for housekeeping functions. Proc. Natl. Acad. Sci. USA 80, 2422–2426.

    Article  PubMed  CAS  Google Scholar 

  • Sved, J., and Bird, A. (1990) The expected equilibrium of the CpG dinucleotide in vertebrate genomes under a mutational model. Proc. Natl. Acad. Sci. USA 87, 4692–4696.

    Article  PubMed  CAS  Google Scholar 

  • Szyf, M., Tanigawa, G., and McCarthy, P. (1990) A DNA signal from the Thy-1 gene defines de novo methylation patterns in embryonic stem cells. Mol. Cell. Biol. 10, 4396–4400.

    PubMed  CAS  Google Scholar 

  • Tazi, J., and Bird, A. (1990) Alternative chromatin structure at CpG islands. Cell 60, 909–920.

    Article  PubMed  CAS  Google Scholar 

  • Toniolo, D., Martini, G., Migeon, B., and Dono, R. (1988) Expression of G6PD locus on the human X chromosome is associated with demethylation of three CpG islands within 100 kb of DNA. EMBO J. 7, 401–406.

    PubMed  CAS  Google Scholar 

  • Tribioli, C., Tamanini, F., Patrosso, C., Milanesi, L., Villa, A., Pergolizzi, R., Maestrini, E., Rivella, S., Bione, S., Mancini, M., Vezzoni, P., and Toniolo, D., (1992) Methylation and sequence analysis around Eagi sites: identification of 28 new CpG islands in XQ24-XQ28. Nucl. Acids Res. 20, 727–733.

    Article  CAS  Google Scholar 

  • Turner, B. (1991) Histone acetylation and control of gene expression. J. Cell Sci. 99, 13–20.

    PubMed  CAS  Google Scholar 

  • Tykocinski, M., and Max, E. (1984) CG dinucleotide clusters in MHC genes and in 5’ demethylated genes. Nucl. Acids Res. 12, 4385–4396.

    Article  PubMed  CAS  Google Scholar 

  • Van der Ploeg, L., and Flavell, R. (1980) DNA methylation in the human gamma-delta-beta- globin locus in erythroid and nonerythroid tissues. Cell 19, 947–958.

    Article  PubMed  Google Scholar 

  • Venolia, L., Gartler, S., Wassman, E., Yen, P., Mohandas, T., and Shapiro, L. (1982) Transformation with DNA from 5-azacytidine-reactivated X chromosomes. Proc. Natl. Acad. Sci. USA 79, 2352–2354.

    Article  PubMed  CAS  Google Scholar 

  • Vincent, A., Heitz, D., Petit, C., Kretz, C., Oberle, I., and Mandel, J. L. (1991) Abnormal pattern detected in fragile X patients by pulsed field gel electrophoresis. Nature 349, 624–626.

    Article  PubMed  CAS  Google Scholar 

  • Watson, R. (1988) A transcriptional arrest mechanism involved in controlling constitutive levels of mouse c-myb mRNA. Oncogene 2, 267–272.

    PubMed  CAS  Google Scholar 

  • Whittaker, P., and Hardman, N. (1980) Methylation of nuclear DNA in Physarum polycephalum. Biochem. J. 191, 859–862.

    PubMed  CAS  Google Scholar 

  • Wiebauer, K., and Jiricny, J. (1990) Mismatch-specific thymine DNA glycosylase and DNA polymerase B mediate the correction of G.T. mispairs in nuclear extracts from human cells. Proc. Natl. Acad. Sci. USA 87, 5842–5845.

    Article  PubMed  CAS  Google Scholar 

  • Wolf, S., Jolly, D., Lunnen, K., Friedman, T., and Migeon, B. (1984) Methylation of the hypoxanthine phosphoribosyltransferase locus on the human X chromosome: Implications for X-chromosome inactivation. Proc. Natl. Acad. Sci. USA 81, 2806–2810.

    Article  PubMed  CAS  Google Scholar 

  • Wolf, S., and Migeon, B. (1985) Clusters of CpG dinucleotides implicated by nuclease hypersensitivity as control elements of housekeeping genes. Nature 314, 467–469.

    Article  PubMed  CAS  Google Scholar 

  • Yang, T., and Caskey, T. (1987) Nuclease sensitivity of the mouse HPRT gene promoter region: Differential sensitivity on the active and inactive X chromosomes. Mol. Cell. Biol. 7, 2994–2998.

    PubMed  CAS  Google Scholar 

  • Yen, P., Patel, P., Chinault, A., Mohandas, T., and Shapiro, L. (1984) Differential methylation of hypoxanthine phosphoribosyltransferase genes on active and inactive human X chromosomes. Proc. Natl. Acad. Sci. USA 81, 1759–1763.

    Article  PubMed  CAS  Google Scholar 

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© 1993 Birkhäuser Verlag Basel/Switzerland

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Antequera, F., Bird, A. (1993). CpG Islands. In: Jost, JP., Saluz, HP. (eds) DNA Methylation. EXS, vol 64. Birkhäuser Basel. https://doi.org/10.1007/978-3-0348-9118-9_8

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  • DOI: https://doi.org/10.1007/978-3-0348-9118-9_8

  • Publisher Name: Birkhäuser Basel

  • Print ISBN: 978-3-0348-9915-4

  • Online ISBN: 978-3-0348-9118-9

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