Abstract
The existence in eukaryotes of a fifth base, 5-methylcytosine, and of tissue-specific methylation patterns have been known for many years, but except for a general association with inactive genes and chromatin the exact function of this DNA modification has remained elusive. The different hypotheses regarding the role of DNA methylation in regulation of gene expression, chromatin structure, development, and diseases, including cancer are summarized, and the experimental evidence for them is discussed. Structural and functional properties of the eukaryotic DNA cytosine methyltransferase are also reviewed.
Similar content being viewed by others
Abbreviations
- Ac:
-
activator
- CRE:
-
cAMP-responsive element
- CREB protein:
-
cAMP-responsive element binding protein
- EC cells:
-
embryocarcinoma cells
- HIV:
-
human immunodeficiency virus
- IGF-II:
-
insulin-like growth factor II
- LTR:
-
long terminal repeat
- 5-mC:
-
5-methyl cytosine
- MDBP:
-
methylated DNA-binding protein
- MeCP:
-
methyl-CpG binding protein
- MEL cells:
-
murine erythroleukemia cells
- NHP-1:
-
non-histone protein-1
- SDR:
-
sequence-specificity determining region
- TF:
-
transcription factor
References
Adams, R. L. P., Gardiner, K., Rinaldi, A., Bryans, M., McGarvey, M., and Burdon, R. H., Mouse ascites DNA methylase: characterisation of size, proteolytic breakdown and nucleotide recognition. Biochim. biophys. Acta868 (1986) 9–16.
Adams, R. L. P., Rinaldi, A., McGarvey, M., Bryans, M., and Ball, K., Eukaryotic DNA methyltransferase: tissue and species distribution. Gene74 (1988) 125–128.
Adams, R. L. P., and So, C. L., Methylation of hen erythrocyte DNA. FEBS Lett.246 (1989) 54–56.
Allen, N. D., Norris, M. L., and Surani, M. A., Epigenetic control of transgene expression and imprinting by genotype-specific modifiers. Cell61 (1990) 853–861.
Antequera, F., Tamame, M., Villanueva, J. R., and Santos, T., DNA methylation in the fungi. J. biol. Chem.259 (1984) 8033–8036.
Antequera, F., and Bird, A., Unmethylated CpG islands associated with genes in higher plant DNA. EMBO J.7 (1988) 2295–2299.
Antequera, F., Macleod, D., and Bird, A., Specific protection of methylated CpGs in mammalian nuclei. Cell58 (1989) 509–517.
Antequera, F., Boyes, J., and Bird, A., High levels of de novo methylation and altered chromatin structure at CpG islands in cell lines. Cell62 (1990) 503–514.
Ball, D. J., Gross, D. S., and Garrard, W. T., 5-Methylcytosine is localized in nucleosomes that contain histone H1. Proc. natl Acad. Sci. USA80 (1983) 5490–5494.
Barlow, D. P., Stöger, R., Herrmann, B. G., Saito, K., and Schweifer, N., The mouse insulin-like growth factor type-2 receptor is imprinted and closely related to the Tme locus. Nature349 (1991) 84–87.
Barr, F. G., Rajagopalan, S., MacArthur, C. A., and Lieberman, M. W., Genomic hypomethylation and far-5′ sequence alterations are associated with carcinogen-induced activation of the hamster thymidine kinase gene. Molec. cell. Biol.6 (1986) 3023–3033.
Becker, P. B., Ruppert, S., and Schütz, G., Genomic footprinting reveals cell type-specific DNA binding of ubiquitous factors. Cell51 (1987) 435–443.
Bednarik D. P., Cook, J. A., and Pitha, P., Inactivation of the HIV LTR by DNA CpG methylation: evidence for a role in latency. EMBO J.9 (1990) 1157–1164.
Bell, M. V., Hirst, M. C., Nakahori, Y., MacKinnon, R. N., Roche, A., Flint, T. J., Jacobs, P. A., Tommerup, N., Tranebjaerg, L., Froster-Iskenius, U., Kerr, B., Turner, G., Lindenbaum, R. H., Winter, R., Pembrey, M., Thibodeau, S., and Davies, K. E., Physical mapping across the fragile X: Hypermethylation and clinical expression of the fragile X syndrome. Cell64 (1991) 861–866.
Benvenisty, N., Mencher, D., Meyuhas, O., Razin, A., and Reshef, L., Sequential changes in DNA methylation patterns of the rat phosphoenolpyruvate carboxykinase gene during development. Proc. natl Acad. Sci.82 (1985), 267–271.
Berg, J. M., Zinc fingers and other metal-binding domains. J. biol. Chem.265 (1990) 6513–6516.
Bernardi, G., The isochore organization of the human genome. A. Rev. Genet.23 (1989) 637–661.
Besser, D., Götz, F., Schulze-Förster, K., Wagner, H., and Simon, H., DNA methylation inhibits transcription by RNA polymerase III of a tRNA gene, but not of a 5S rRNA gene. FEBS Lett.269 (1990) 358–362.
Bestor, T. H., Supercoiling-dependent sequence specificity of mammalian DNA methyltransferase. Nucl. Acids Res.15 (1987) 3835–3843.
Bestor, T. H., and Ingram, V. M., Two DNA methyltransferases from murine erythroleukemia cells: purification, sequence specificity, and mode of interaction with DNA. Proc. natl Acad. Sci.80 (1983) 5559–5563.
Bestor, T. H., Hellewell, S. B., and Ingram, V. M., Differentiation of two mouse cell lines is associated with hypomethylation of their genomes. Molec. cell. Biol.4 (1984) 1800–1806.
Bestor, T. H., and Ingram, V. M., Growth-dependent expression of multiple species of DNA methyltransferase in murine erythroleukemia cells. Proc. natl Acad. Sci.82 (1985) 2674–2678.
Bestor, T. H., Laudano, A., Mattaliano, R., and Ingram, V., Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. J. molec. Biol.203 (1988) 971–983.
Bird, A. P., DNA methylation and the frequency of CpG in animal DNA. Nucl. Acids. Res.8 (1980) 1499–1504.
Bird, A. P., CpG-rich islands and the function of DNA methylation. Nature321 (1986) 209–213.
Bird, A. P., Taggart, M. H., and Smith, B. A., Methylated and unmethylated DNA compartments in the sea urchin genome. Cell17 (1979) 889–901.
Bird, A. P., and Taggart, M. H., Variable patterns of total DNA and rDNA methylation in animals. Nucl. Acids Res.8 (1980) 1485–1497.
Bird, A., Taggart, M., Frommer, M., Miller, O. J., and Macleod, J., A fraction of the mouse genome that is derived from islands of nonmethylated CpG-rich DNA. Cell40 (1985) 91–99.
Bird, A., Taggart, M. H., Nicholls, R., and Higgs, D. R., Nonmethylated CpG-rich islands at the human α-globin locus: implications for evolution of the α-globin pseudogene. EMBO J.6 (1987) 999–1004.
Bolden, A., Ward, C., Siedlecki, J. A., and Weissbach, A., DNA methylation: Inhibition of de novo and maintenance methylation in vitro by RNA and synthetic polynucleotides. J. biol. Chem.259 (1984) 12437–12443.
Boshart, M., Weber, F., Jahn, G., Dorsch-Häsler, K., Fleckenstein, B., and Schaffner, W., A very strong enhancer is located upstream of an immediate early gene of human cytomegalovirus. Cell41 (1985) 521–530.
Boye, E., and Löbner-Olesen, A., The role of the dam methyltransferase in the control of DNA replication in E. coli. Cell62 (1990) 981–989.
Boyes, J., and Bird, A., DNA methylation inhibits transcription indirectly via a methyl-CpG binding protein. Cell64 (1991) 1123–1134.
Burbelo, P. D., Horikoshi, S., and Yamada, Y., DNA methylation and collagen IV gene expression in F9 teratocarcinoma cells. J. biol. Chem.265 (1990) 4839–4843.
Buschhausen, G., Wittig, B., Graessmann, M., and Graessmann, A., Chromatin structure is required to block transcription of the methylated herpes simplex virus thymidine kinase gene. Proc. natl Acad. Sci.84 (1987) 1177–1181.
Busslinger, M., Hurst, J., and Flavell, R. A., DNA methylation and the regulation of globin gene expression. Cell34 (1983) 197–206.
Campbell, J. L., and Kleckner, N., E. colioriC and thednaA gene promoter are sequestered fromdam methyltransferase following the passage of the replication fork. Cell62 (1990) 967–979.
Carotti, D., Palitti, F., Lavia, P., and Strom, R., In vitro methylation of CpG-rich islands. Nucl. Acids Res.17 (1989) 9219–9229.
Cattanach, B. M., and Beechy, C. V., Autosomal and X-chromosome imprinting, in: Genomic Imprinting, pp. 63–72. Eds M. Monk and M. A. Surani. Development 1990 Supplement.
Cedar, H., DNA methylation and gene activity. Cell53 (1988) 3–4.
Cedar, H., and Razin, A., DNA methylation and development. Biochim. biophys. Acta1049 (1990) 1–8.
Chandler, L. A., Ghazi, H., Jones, P. A., Boukamp, P., and Fusenig, N. E., Allele-specific methylation of the human c-Ha-ras-1 gene. Cell50 (1987) 711–717.
Chargaff, E., Lipshitz, R., and Green, C., Composition of the desoxypentose nucleic acids of four genera of sea-urchin. J. biol. Chem.195 (1952) 155–160.
Church, G. M., and Gilbert, W., Genomic sequencing. Proc. natl Acad. Sci. USA81 (1984) 1991–1995.
Comb, M., and Goodman, H. M., CpG methylation inhibits proenkephalin gene expression and binding of the transcription factor AP-2. Nucl. Acids Res.18 (1990) 3975–3982.
Coulondre, C., Miller, J. H., Farabaugh, P. J., and Gilbert, W., Molecular basis of base substitution hotspots inEscherichia coli. Nature274 (1978) 775–780.
Dawid, I. B., Deoxyribonucleic acid in amphibian eggs. J. molec. Biol.12 (1962) 581–599.
De Bustros, A., Nelkin, B. D., Silverman, A., Ehrlich, G., Poiesz, B., and Baylin, S. B., The short arm of chromosome 11 is a ‘hot spot’ for hypermethylation in human neoplasia. Proc. natl Acad. Sci. USA85 (1988) 5693–5697.
DeChiara, T. M., Robertson, E. J., and Efstratiadis, A., Parental imprinting of the mouse insulin-like growth factor II gene. Cell64 (1991) 849–859.
Dellaporta, S. L., Chomet, P. S., Mottinger, J. P., Wood, J. A., Yu, S.-M., and Hicks, J. B., Endogenous transposable elements associated with virus infection in maize. Cold Spring Harbor Symp. quant. Biol.49 (1984) 321–328.
Deobagkar, D. D., Liebler, M., Graessmann, M., and Graessmann, A., Hemimethylation of DNA prevents chromatin expression. Proc. natl Acad. Sci.87 (1990) 1691–1695.
Drahovsky, D. and Morris, N. R., Mechanism of action of rat liver DNA methylase. I. Interaction with double-stranded methyl-acceptor DNA. J. molec. Biol.57 (1971) 475–489.
Drahovsky, D., and Pfeifer, G. P., Enzymology of DNA methylation in mammalian cells, in: Architecture of Eukaryotic Genes, pp. 435–445. Ed. G. Kahl. VCH, Weinheim 1988.
Driscoll, D. J., and Migeon, B. R., Sex differences in methylation of single-copy genes in human meiotic germ cells: implications for X chromosome inactivation, parental imprinting, and origin of CpG mutations. Som. Cell. Genet.16 (1990) 267–282.
Dryja, T. P., Mukai, S., Petersen, R., Rapaport, J. M., Walton, D., and Yandell, D. W., Parental origin of mutations of the retinoblastoma gene. Nature339 (1989) 556–558.
Ehrlich, M., Gama-Sosa, M. A., Huang, L., Midgett, R. M., Kuo, K. C., McCune, R. A., and Gehrke, C., Amount and distribution of 5-methyl-cytosine in human DNA from different types of tissues or cells. Nucl. Acids Res.10 (1982) 2709–2721.
Enver, T., Zhang, J., Papayannopoulou, T., and Stamatoyannopoulos, G., DNA methylation: a secondary event in globin gene switching? Genes Devl.2 (1988) 698–706.
Falzon, M., and Kuff, E. L., Binding of the transcription factor EBP-80 mediates the methylation response of an intracisternal Aparticle long terminal repeat promoter. Molec. cell. Biol.11 (1991) 117–125.
Fearon, E. R., and Vogelstein, B., A genetic model for colorectal tumorigenesis. Cell61 (1990) 759–767.
Feinberg, A. P., and Vogelstein, B., Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature301 (1983) 89–92.
Frank, D., Lichtenstein, M., Paroush, Z., Bergman, Y., Shani, M., Razin, A., and Cedar, H., Demethylation of CpG islands in embryonic cells. Phil. Trans. R. Soc. Lond. B326 (1990) 241–251.
Gama-Sosa, M. A., Midgett, R. M., Slagel, V. A., Githens, S., Kuo, K. C., Gehrke, C., and Ehrlich, M., Tissue-specific differences in DNA methylation in various mammals. Biochim. biophys. Acta740 (1983) 212–219.
Gama-Sosa, M. A., Wang, R. Y.-H., Kuo, K. C., Gehrke, C., and Ehrlich, M., The 5-methylcytosine content of highly repeated sequences in human DNA. Nucl. Acids Res.11 (1983) 3087–3095.
Gama-Sosa, M. A., Trewyn, R. W., Oxenhandler, R., Kuo, K. C., Gehrke, C., and Ehrlich, M., The 5-methylcytosine content of DNA from human tumors. Nucl. Acids Res.11 (1983) 6883–6894.
Gardiner-Garden, M., and Frommer, M., CpG islands in vertebrate genomes. J. molec. Biol.196 (1987) 261–282.
Gautsch, W. J., and Wilson, M. C., Delayed de novo methylation in teratocarcinoma suggests additional tissue-specific mechanisms for controlling gene expression. Nature301 (1983) 32–37.
Gerber-Huber, S., May, F. E. B., Westley, B. R., Felber, B. K., Hosbach, H. A., Andres, A.-C., and Ryffel, G. U., In contrast to other Xenopus genes the estrogen-inducible vitellogenin genes are expressed when totally methylated. Cell33 (1983) 43–51.
Ghazi, H., Magewu, A. N., Gonzales, F., and Jones, P. A., Changes in the allelic methylation patterns of c-H-ras-1, insulin and retinoblastoma genes in human development, in: Genomic Imprinting, pp. 115–124. Eds M. Monk and M. A. Surani. Development 1990 Supplement.
Gierl, A., Lütticke, S., and Saedler, H., TnpA product encoded by the transposable element En-1 of Zea mays is a DNA binding protein. EMBO J.7 (1988) 4045–4053.
Goelz, S. E., Vogelstein, B., Hamilton, S. R., and Feinberg, A. P., Hypomethylation of DNA from benign and malignant human colon neoplasms. Science228 (1985) 187–190.
Gönczy, P., Reith, W., Barras, E., Lisowska-Grospierre, B., Griscelli, C., Hadam, M. R., and Mach, B., Inherited immunodeficiency with a defect in a major histocompatibility complex class II promoter-binding protein differs in the chromatin structure of the HLA-DRA gene. Molec. cell. Biol.9 (1989) 296–302.
Grant, S. G., and Chapman, V. M., Mechanism of X-chromosome regulation. A. Rev. Genet.22 (1988) 199–233.
Green, P. M., Montandon, A. J., Bentley, D. R., Ljung, R., Nilsson, I. M., and Giannelli, F., The incidence and distribution of CpG-TpG transitions in the coagulation factor IX gene. A fresh look at CpG mutational hotspots. Nucl. Acids Res.18 (1990) 3227–3231.
Gross, D. S., and Garrard, W. T., Nuclease hypersensitive sites in chromatin. A. Rev. Biochem.57 (1988) 159–197.
Groudine, M., and Conkin, K. F., Chromatin structure and de novo methylation of sperm DNA: implications for activation of the paternal genome. Science228 (1985) 1061–1068.
Gruenbaum, Y., Naveh-Many, T., Cedar, H., and Razin, A., Sequence specificity of methylation in higher plant DNA. Nature292 (1981) 860–862.
Gruenbaum, Y., Cedar, H., and Razin, A., Substrate and sequence specificity of a eukaryotic DNA methylase. Nature295 (1982) 620–622.
Gruenbaum, Y., Szyf, M., Cedar, H., and Razin, A., Methylation of replicating and post-replicated mouse L-cell DNA. Proc. natl Acad. Sci. USA80 (1983) 4919–4921.
Hall, J. G., How imprinting is relevant to human disease, in: Genomic Imprinting, pp. 141–149. Eds M. Monk and M. A. Surani. Development 1990 Supplement.
Harrington, M. A., Jones, P. A., Imagawa, M., and Karin, M., Cytosine methylation does not affect binding of transcription factor Sp1. Proc. natl Acad. Sci. USA85 (1988) 2066–2070.
Heitz, D., Rousseau, F., Devys, D., Saccone, S., Abderrahim, H., Le Paslier, D., Cohen, D., Vincent, A., Toniolo, D., Della Valle, G., Johnson, S., Schlessinger, D., Oberlé, I., and Mandel, J. L., Isolation of sequences that span the fragile X and identification of a fragile X-related CpG island. Science251 (1991) 1236–1239.
Hermann, R., and Doerfler, W., Interference with protein binding at AP2 sites by sequence-specific methylation in the late E2A promoter of adenovirus type 2 DNA. FEBS Lett.281 (1991) 191–195.
Hitt, M. M., Wu, T. L., Cohen, G., and Linn, S.,De novo and maintenance DNA methylation by a mouse plasmacytoma cell DNA methyltransferase. J. biol. Chem.263 (1988) 4392–4399.
Ho, L., Bohr, V. A., and Hanawalt, P. C., Demethylation enhances removal of pyrimidine dimers from the overall genome and from specific DNA sequences in Chinese hamster ovary cells. Molec. cell. Biol.9 (1989) 1594–1603.
Höller, M., Westin, G., Jiricny, J., and Schaffner, W., Sp1 transcription factor binds DNA and activates transcription even when the binding site is CpG methylated. Genes Devl.2 (1988) 1127–1135.
Holliday, R., The inheritance of epigenetic defects. Science238 (1987) 163–170.
Holliday, R., Monk, M., and Pugh, J. E. (eds), DNA Methylation and Gene Regulation. The Royal Society 1990.
Hsiao, W. W., Gattoni-Celli, S., Kirschmeier, P., and Weinstein, I. B., Effects of 5-azacytidine on methylation and expression of specific DNA sequences in C3H 10T1/2 cells. Molec. cell. Biol.4 (1984) 634–641.
Huang, L.-H., Wang, R., Gama-Sosa, M. A., Shenoy, S., and Ehrlich, M., A protein from human placental nuclei binds preferentially to 5-methylcytosine-rich DNA. Nature308 (1984) 293–295.
Hubrich-Kühner, K., Buhk, H.-J., Wagner, H., Kröger, H., and Simon, D., Non-C-G recognition sequences of DNA cytosine-5-methyltransferase from rat liver. Biochem. biophys. Res. Commun.160 (1989) 1175–1182.
Hughes, M. J., Liang, H., Jiricny J., and Jost, J.-P., Purification and characterization of a protein from HeLa cells that binds with high affinity to the estrogen response element, GGTCAGCGTGACC. Biochemistry28 (1989) 9137–9142.
Iguchi-Ariga, S. M. M., and Schaffner, W., CpG methylation of the cAMP-responsive enhancer/promoter sequence TGACGTCA abolishes specific factor binding as well as transcriptional activation. Genes Devl.3 (1989) 612–619.
Ip, Y. T., Granner, D. K., and Chalkley, R., Hormonal induction of phosphoenolpyruvate carboxykinase gene expression is mediated through modulation of an already disrupted chromatin structure. Molec. cell. Biol.9 (1989) 1289–1297.
Jablonka, E., Goitein, R., Marcus, M., and Cedar, H., DNA hypomethylation causes an increase in DNase-I sensitivity and an advance in the time of replication of the entire inactive X chromosome. Chromosoma93 (1985) 152–156.
Jadayel, D., Fain, P., Upadhyaya, M., Ponder, M. A., Huson, S. M., Carey, J., Fryer, A., Mathew, C. G. P., Barker, D. F., and Ponder, B. A. J., Paternal origin of new mutations in von Recklinghausen neurofibromatosis. Nature343 (1990) 558–559.
Jaenisch, R., and Jähner, D., Methylation, expression and chromosomal position of genes in mammals. Biochim. biophys. Acta782 (1984) 1–9.
Jones, P. A., Altering gene expression with 5-azacytidine. Cell40 (1985) 485–486.
Jones, P. A., Wolkowicz, M. J., Rideout III, W. M., Gonzales, F. A., Marziasz, C. M., Coetzee, G. A., and Tapscott, S. J.,De novo methylation of the MyoD1 CpG island during the establishment of immortal cell lines. Proc. natl Acad. Sci. USA,87 (1990) 6117–6121.
Jongstra, J., Reudelhuber, T. L., Oudet, P., Benoist, C., Chae, C.-B., Jeltsch, J.-M., Mathis, D., and Chambon, P., Induction of altered chromatin structures by simian virus 40 enhancer and promoter elements. Nature307 (1984) 708–714.
Jüttermann, R., Hosokawa, K., Kochanek, S., and Doerfler, W., Adenovirus type 2 VAI RNA transcription by polymerase III is blocked by sequence-specific methylation. J. Virol.65 (1991) 1735–1742.
Kageyama, R., Merlino, G. T., and Pastan, I., Nuclear factor ETF specifically stimulates transcription from promoters without a TATA box. J. biol. Chem.264 (1989) 15508–15514.
Kageyama, R., and Pastan, I., Molecular cloning and characterization of a human DNA binding factor that represses transcription. Cell59 (1989) 815–825.
Kastan, M. B., Gowans, B. J., and Lieberman, M. W., Methylation of deoxycytidine incorporated by excision-repair synthesis of DNA. Cell30 (1982) 509–516.
Kautiainen, T. L., and Jones, P. A., DNA methyltransferase levels in tumorigenic and nontumorigenic cells in culture. J. biol. Chem.261 (1986) 1594–1598.
Kelley, D. E., Pollak, B. A., Atchison, M., and Perry, R. P., The coupling between enhancer activity and hypomethylation of κ immunoglobulin genes is developmentally regulated. Molec. cell. Biol.8 (1988) 930–937.
Keshet, I., Liemann-Hurwitz, J., and Cedar, H., DNA methylation affects the formation of active chromatin. Cell44 (1986) 535–543.
Knebel-Mörsdorf, D., Achten, S., Langner, K.-D., Rüger, R., Fleckenstein, B., and Dörfler, W., Reactivation of the methylation-inhibited late E2A promoter of adenovirus type 2 by a strong enhancer of human cytomegalovirus. Virology166 (1988) 166–174.
Kolsto, A.-B., Kollias, G., Giguere, V., Isobe, K.-I., Prydz, H., and Grosveld, F., The maintenance of methylation-free islands in transgenic mice. Nucl. Acids Res.14 (1986) 9667–9678.
Kovesdi, I., Reichel, R., and Nevins, J. R., Role of an adenovirus E2 promoter binding factor in E1A-mediated coordinate gene control. Proc. natl Acad. Sci.84 (1987) 2180–2184.
Kunze, R., and Starlinger, P., The putative transposase of transposable element Ac fromZea mays L. interacts with subterminal sequences of Ac. EMBO J.8 (1989) 3177–3185.
Lamson, G., and Stockdale, F. E., Developmental and musclespecific changes in methylation of the myosin light chain LV1f and LC3f promoters during avian myogenesis. Devl. Biol.132 (1989) 62–68.
Landousi, A., Malki, A., Kern, R., Kohiyama, M., and Hughes, P., TheE. coli surface specifically prevents the initiation of DNA replication at oriC on hemimethylated DNA templates. Cell63 (1990) 1053–1060.
Lieberman, M. W., Beach, L. R., and Palmiter, R. D., Ultraviolet radiation-induced metallothionein-I gene activation is associated with extensive DNA demethylation. Cell35 (1983) 207–214.
Lock, L. F., Takagi, N., and Martin, G. R., Methylation of the Hprt gene on the inactive X occurs after chromosome inactivation. Cell48 (1987) 39–46.
Lyon, S. B., Buonocore, L., and Miller, M., Naturally occurring methylation inhibitor: DNA hypomethylation and hemoglobin synthesis in human K562 cells. Molec. cell. Biol.7 (1987) 1759–1763.
McCarthy, J., The evolution of base sequences in polynucleotides. Prog. nucl. Acid Res. molec. Biol.4 (1965) 129–160.
McClelland, M., and Nelson, M., The effect of site-specific methylation on restriction endonucleases and DNA modification methyltransferases a review. Gene74 (1988) 291–304.
McClintock, B., The significance of responses of the genome to challenge. Science226 (1984) 792–801.
McGowan, R., Campbell, R., Peterson, A., and Sapienza, C., Cellular mosaicism in the methylation and expression of hemizygous loci in the mouse. Genes Devl.3 (1989) 1669–1676.
Macleod, D., and Bird, A., Transcription in oocytes of highly methylated rDNA fromXenopus laevis sperm. Nature306 (1984) 200–203.
Magenis, E. R., Toth-Fejel, S., Allen, L. J., Black, M., Brown, M. G., Budden, S., Cohen, R., Friedman, J. M., Kalousek, D., Zonana, J., Lacey, D., LaFranchi, S., Lahr, M., MacFarlane, J., and Williams, C. P. S., Comparison of the 15q deletions in Prader-Willi and Angelman syndromes: specific regions, extent of deletions, parental origin, and clinical consequences. Am. J. Hum. Genetics35 (1990) 333–349.
Martienssen, R., Barkan, A., Taylor, W. C., and Freeling, M., Somatically heritable switches in the DNA modification of Mu transposable elements monitored with a suppressible mutant in maize. Genes Devl.4 (1990) 331–343.
Mays-Hoopes, L. L., Age-related changes in DNA methylation: do they represent continued developmental changes? Int. Rev. Cytol.114 (1989) 181–220.
Means, A. L., and Farnham, P. J., Transcription initiation from the dihydrofolate reductase promoter is positioned by HIP1 binding at the initiation site. Molec. cell. Biol.10 (1990) 653–661.
Meehan, R. R., Lewis, J. D., McKay, S., Kleiner, E. L., and Bird, A., Identification of a mammalian protein that binds specifically to DNA containing methylated CpGs. Cell58 (1989) 499–507.
Mehtali, M., LeMeur, M., and Lathe, R., The methylation-free status of a housekeeping transgene is lost at high copy number. Gene91 (1990) 179–184.
Migeon, B. R., Axelman, J., and Beggs, A. H., Effect of ageing on reactivation of the human X-linked HPRT locus. Nature335 (1988) 93–96.
Milici, A., Salbaum, J. M., and Beyreuther, K., Study of the Alzheimer's A4 precursor gene promoter region by genomic sequencing using Taq polymerase. Biochem. biophys. Res. Commun.169 (1990) 46–50.
Mitchell, P. J., and Tjian, R., Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins. Science245 (1989) 371–378.
Monk, M., Boubelik, M., and Lehnert, S., Temporal and regional changes in DNA methylation in the embryonic, extraembryonic and germ cell lineages during mouse embryo development. Development99 (1987) 371–382.
Monk, M., Changes in DNA methylation during mouse development in relation to X-chromosome activity and imprinting. Phil. Trans. R. Soc. Lond. B326 (1990) 299–312.
Monk, M., and Surani, M. A., (eds), Genomic Imprinting. Development 1990 Supplement.
Murray, E., and Grosveld, F., Site specific demethylation in the promoter of human γ-globin gene does not alleviate methylation mediated suppression. EMBO6 (1987) 2329–2335.
Nagl, W., Zellkern und Zellzyklen, p. 16. Verlag Eugen Ulmer, Stuttgart 1976.
Naveh-Maneh, T., and Cedar, H., Topographical distribution of 5-methylcytosine in animal and plant DNA. Molec. cell. Biol.2 (1982) 758–762.
Nick, H., Bowen, B., Ferl, R. J., and Gilbert, W., Detection of cytosine methylation in the maize alcohol dehydrogenase gene by genomic sequencing. Nature319 (1986) 243–246.
Noguchi, H., Prem veer Reddy, G., and Pardee, A. B., Rapid incorporation of label from ribonucleoside diphosphates into DNA by a cell-free high molecular weight fraction from animal cell nuclei. Cell32 (1983) 443–451.
Ott, M., Sperling, L., Cassio, D., Levilliers, J., Sala-Trepat, J., and Weiss, M. C., Undermethylation at the 5′ end of the albumin gene is necessary but not sufficient for albumin production by rat hepatoma cells in culture. Cell30 (1982) 825–833.
Pagani, F., Toniolo, D., and Vergani, C., Stability of DNA methylation of X-chromosome genes during aging. Somat. cell. molec. Genet.16 (1990) 79–84.
Palmgren, G., Mattsson, O., and Okkels, F. T., Employment of hydrolytic enzymes in the study of the level of DNA methylation. Biochim. biophys. Acta1049 (1990) 293–297.
Paroush, Z., Keshet, I., Yisraeli, J., and Cedar, H., Dynamics of demethylation and activation of the a-catin gene in myoblasts. Cell63 (1990) 1229–1237.
Pawlak, A., Bryans, M., and Jost, J.-P., An avian 40 kDa nucleoprotein binds preferentially to a promoter sequence containing one single pair of methylated CpG. Nucl. Acids Res.19 (1991) 1029–1034.
Peschke, V. M., Phillips, R. L., and Gengenbach, B. G., Discovery of transposable element activity among progeny of tissue culture-derived maize plants. Science238 (1987) 804–807.
Pfeifer, G. P., Grünwald, S., Boehm, T. L. J., and Drahovsky, D., Isolation and characterisation of DNA-cytosine-5-methyltransferase from human placenta. Biochim. biophys. Acta740 (1983) 323–330.
Pfeifer, G. P., Spiess, E., Grünwald, S., Boehm, T. L. J., and Drahovsky, D., Mouse DNA-cytosine-5-methyltransferase: sequence specificity of the methylation reaction and electron microscopy of enzyme-DNA complexes. EMBO J.4 (1985) 2879–2884.
Pfeifer, G. P., Grünwald, S., Palitti, F., Kaul, S., Boehm, T. L. J., Hirth, H.-P., and Drahovsky, D., Purification and characterization of mammalian DNA methyltransferase by use of monoclonal antibodies. J. biol. Chem.260 (1985) 13787–13793.
Pfeifer, G. P., and Drahovsky, D., DNA methyltransferase polypeptides in mouse and human cells. Biochim. biophys. Acta868 (1986) 238–242.
Pfeifer, G. P., Steigerwald, S. D., Mueller, P. R., Wold, B., and Riggs, A. D., Genomic sequencing and methylation analysis by ligation mediated PCR. Science246 (1989) 810–813.
Pfeifer, G. P., Tanguay, R. L., Steigerwald, S. D., and Riggs, A. D., 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 Devl.4 (1990) 1277–1287.
Pfeifer, G. P., Steigerwald, S. D., Hansen, R. S., Gartler, S. M., and Riggs, A. D., Polymerase chain reaction-aided genomic sequencing of an X chromosome-linked CpG island: methylation patterns suggest clonal inheritance, CpG site autonomy, and an explanation of activity state stability. Proc. natl Acad. Sci. USA87 (1990) 8253–8256.
Pösfai, J., Bhagwat, A. S., Posfai, G., and Roberts, R. J., Predictive motifs derived from cytosine methyltransferases. Nucl. Acids Res.17 (1989) 2421–2435.
Poethig, R. S., Phase change and the regulation of shoot morphogenesis in plants. Science250 (1990) 923–930.
Prendergast, G. C., and Ziff, E. B., Methylation-sensitive sequencespecific DNA binding by the c-myc basic region. Science251 (1991) 186–189.
Profitt, J. H., Davie, J. R., Swinton, D., and Hattman, S., 5-Methylcytosine is not detectable in Saccharomyces cerevisiae DNA. Molec. cell. Biol.4 (1984) 985–988.
Quigley, F., Brinkmann, H., Martin, W. F., and Cerff, R., Strong functional GC pressure in a light-regulated maize gene encoding subunit GAPA of chloroplast glyceraldehyde-3-phosphate dehydrogenase: implications for the evolution of GAPA pseudogenes. J. molec. Evol.29 (1989) 412–421.
Razin, A., DNA methylases, in: Genetic Engineering 11, pp. 1–12. Ed. J. Setlow. Plenum Press, New York 1988.
Razin, A., and Szyf, M., DNA methylation patterns. Formation and function. Biochim. biophys. Acta782 (1984) 331–342.
Razin, A., Webb, C., Szyf, M., Yisraeli, J., Rosenthal, A., Naveh-Many, T. Sciaky-Gallili, N., and Cedar, H., Variations in DNA methylation during mouse cell differentiation in vivo and in vitro. Proc. natl Acad. Sci.81 (1984) 2275–2279.
Razin, A., Szyf, M., Kafri, T., Roll, H., Scarpa, S., Carotti, D., and Cantoni, G., Replacement of 5-methylcytosine by cytosine: A possible mechanism for transient DNA demethylation during differentiation. Proc. natl Acad. Sci.83 (1986) 2827–2881.
Razin, A., Levine, A., kafri, T., Agostini, S., Gomi, T., and Cantoni, G. L., Relationship between transient DNA hypomethylation and erythroid differentiation of murine erythroleukemia cells. Proc. natl Acad. Sci.85 (1988) 9003–9006.
Rees, H., and Jones, R. N., The origin of the wide species variation in nuclear DNA content. Int. Rev. Cytol.32 (1972) 53–92.
Reik, W., Genomic imprinting and genetic disorders in man. Trends Genet.5 (1989) 331–336.
Reik, W., and Surani, M. A., Cancer genetics: genomic imprinting and embryonal tumours. Nature338 (1989) 112–113.
Reik, W., Howlett, S. K., and Surani, M. A., Imprinting by DNA methylation: from transgenes to endogenous gene sequences, in: Genomic Imprinting, pp. 99–106. Eds M. Monk and M. A. Surani. Development 1990 Supplement.
Rideout III, W. M., Coetzee, G. A., Olumi, A. F., and Jones, P. A., 5-Methylcytosine as an endogenous mutagen in the human LDL receptor and p53 genes. Science249 (1990) 1288–1290.
Rothnie, H. M., McCurrach, K. J., Glover, L. A., and Hardman, N., Retrotransposon-like nature of Tp1 elements: implications for the organisation of highly repetitive, hypermethylated DNA in the genome ofPhysarum polycephalum. Nucl. Acids Res.19 (1991) 279–286.
Russell, P. J., Rodland, K. D., Rachlin, E. M., and McCloskey, J. A., Differential DNA methylation during the vegetative life cycle ofNeurospora crassa. J. Bact.169 (1987) 2902–2905.
Saluz, H. P., Jiricny, J., and Jost, J. P., Genomic sequencing reveals a positive correlation between the kinetics of strand-specific DNA demethylation of the overlapping estradiol/glucocorticoid-receptor binding sites and the rate of avian vitellogenin mRNA synthesis. Proc. natl Acad. Sci. USA83 (1986) 7167–7171.
Saluz, H. P., Feavers, I. M., Jiricny, J., and Jost, J. P., Genomic sequencing and in vivo footprinting of an expression-specific DNAse I-hypersensitive site of avian vitellogenin II promoter reveal a demethylation of a mCpG and a change in specific interactions of proteins with DNA. Proc. natl Acad. Sci. USA85 (1988) 6697–6700.
Sanford, J. P., Chapman, V. M., and Rossant, J., DNA methylation in extraembryonic lineages of mammals. Trends Genet.1 (1985) 89–93.
Sanford, J. P., Clark, H. J., Chapman, V. M., and Rossant, J., Differences in DNA methylation during oogenesis and spermatogenesis and their persistence during early embryogenesis in the mouse. Genes Devl1 (1987) 1039–1046.
Santi, D. V., Garrett, C. E., and Barr, P. J., On the mechanism of inhibition of DNA-cytosine methyltransferases by cytosine analogs. Cell33 (1983) 9–10.
Sapienza, C., Paquette, J., Tran, T. H., and Peterson, A., Epigenetic and genetic factors affect transgene methylation imprinting. Development107 (1989) 165–168.
Sasaki, H., Hamada, T., Ueda, T., Seki, R., Higashinakagawa, T., and Sakaki, Y., Inherited type of allelic methylation variations in a mouse chromosome region where an integrated transgene shows methylation imprinting. Development111 (1991) 573–581.
Schulze-Forster, K., Götz, F., Wagner, H., Kröger, H., and Simon, D., Transcription of HIV1 is inhibited by DNA methylation. Biophys. biochem. Res. Comm.168 (1990) 141–147.
Selig, S., Ariel, M., and Cedar, H., Regulation of mouse satellite DNA replication time. EMBO J.7 (1988) 419–426.
Selker, E. U., Premeiotic instability of repeated sequences inNeurospora crassa. A. Rev. Genetics24 (1990) 579–613.
Shen, E. S., and Whitlock, J. P., The potential role of DNA methylation in the response to 2,3,7,8-tetrachlorodibenzo-p-dioxin. J. biol. Chem.264 (1989) 17754–17758.
Shimada, T., Inokuchi, K., and Nienhuis, A. W., Site-specific demethylation and normal chromatin structure of the human dihydrofolate reductase gene promoter after transfection into CHO cells. Molec. cell. Biol.7 (1987) 2830–2837.
Shpaer, E. G., and Mullins, J. I., Selection against CpG nucleotides in lentiviral genes: a possible role of methylation in regulation of viral expression. Nucl. Acids. Res.18 (1990) 5793–5797.
Silva, A. J., and White, R., Inheritance of allelic blueprints for methylation patterns. Cell54 (1988), 145–152.
Simon, D., Grunert, F., v. Acken, U., Döring, H. P., and Kröger, H., DNA-methylase from regenerating rat liver: purification and characterization. Nucl. Acids Res.5 (1978) 2153–2167.
Singh, P. B., Miller, J. R., Pearce, J., Kothary, R., Burton, R. D., Paro, R., James, T. C., and Gaunt, S. J., A sequence motif found in aDrosophila heterochromatin protein is conserved in animals and plants. Nucl. Acids Res.19 (1991) 789–794.
Solter, D., Differential imprinting and expression of maternal and paternal genomes. A. Rev. Genetics22 (1988) 127–146.
Spiess, E., Tomassetti, A., Hernaiz-Driever, P., and Pfeifer, G. P., Structure of mouse DNA (cytosine-5-)-methyltransferase. Eur. J. Biochem.177 (1988) 29–34.
Staiger, D., Kaulen, H., and Schell, J., A CACGTG motif of the Antirrhinum majus chalcone synthase promoter is recognized by an evolutionarily conserved nuclear protein. Proc. natl Acad. Sci.86 (1989) 6930–6934.
Stein, B., Rahmsdorf, H. J., Steffen, A., Litfin, M., and Herrlich, P., UV-induced DNA damage is an intermediate step in the UV-induced expression of human immunodeficiency virus type 1, collagenase, c-fos, and metallothionein. Molec. cell. Biol.9 (1989) 5169–5181.
Sullivan, C. H., and Grainger, R. M., δ-crystallin genes become hypomethylated in postmitotic lens cells during chicken development. Proc. natl Acad. Sci. USA83 (1986) 329–333.
Surani, M. A., Kothary, R., Allen, N. D., Singh, P. B., Fundele, R., Ferguson-Smith, A. C., and Barton, S. C., Genome imprinting and development in the mouse, in: Genomic Imprinting, pp. 89–99. Eds M. Monk and M. A. Surani. Development 1990 Supplement.
Swain, J. L., Stewart, T. A., and Leder, P., Parental legacy determines methylation and expression of an autosomal transgene: a molecular mechanism for parental imprinting. Cell50 (1987) 719–727.
Szyf, M., Avraham-Haetzni, K., Reifman, A., Shlomai, J., Kaplan, F., Oppenheim, A., and Razin, A., DNA methylation is determined by the intracellular level of the methylase. Proc. natl Acad. Sci. USA81 (1984) 3278–3282.
Szyf, M., Eliasson, L., Mann, V., Klein, G., and Razin, A., Cellular and viral DNA hypomethylation associated with induction of Epstein-Barr virus lytic cycle. Proc. natl Acad. Sci. USA82 (1985) 8090–8094.
Szyf, M., Tanigawa, G., and McCarthy, P. L. Jr., A DNA signal from the Thy-1 gene defines de novo methylation patterns in embryonic stem cells. Molec. cell. Biol.10 (1990) 4396–4400.
Tazi, J., and Bird, A., Alternative chromatin structure at CpG islands. Cell60 (1990) 909–920.
Tomassetti, A., Driever, P. H., Pfeifer, G. P., and Drahovsky, D., Isolation and characterization of proteins that stimulate the activity of mammalian DNA methyltransferase. Biochim. biophys. Acta951 (1988) 201–212.
Toth, M., Müller, U., and Doerfler, W., Establishment ofde novo DNA methylation patterns. Transcription factor binding and deoxycytidine methylation at CpG and non-CpG sequences in an integrated adenovirus promoter. J. molec. Biol.214 (1990) 673–683.
Urieli-Shoval, S., Gruenbaum, Y., Sedat, J., and Razin, A., The absence of detectable methylated bases inDrosophila melanogaster DNA. FEBS Lett.146 (1981) 148–152.
Valerie, K., and Rosenberg, M., Chromatin structure implicated in activation of HIV-1 gene expression by ultraviolet light. The New Biologist2 (1990) 712–718.
Vanyushin, B. F., Tkacheva, S. G., and Belozersky, A. N., Rare bases in animal DNA. Nature225 (1970) 948–949.
Vincent, A., Heitz, D., Petit, C., Kretz, C., Oberlé, I., and Mandel, J.-L., Abnormal pattern detected in fragile-X patients by pulsed-field gel electrophoresis. Nature349 (1991) 624–626.
Waalwijk, C., and Flavell, R. A., MspI, an isoschizomer of HpaII which cleaves both unmethylated and methylated HpaII sites. Nucl. Acids Res.5 (1978) 3231–3236.
Walbot, V., Reactivation of the Mutator transposable element system following gamma irradiation of seed. Molec. gen. Genet.212 (1988) 259–264.
Walter, J., Noyer-Weidner, M., and Trautner, T. A., The amino acid sequence of the CCGG recognizing DNA methyltransferase M. Bsu-FI: implications for the analysis of sequence recognition by cytosine DNA methyltransferases. EMBO J.9 (1990) 1007–1013.
Wareham, K. A., Lyon, M. F., Glenister, P. H., and Williams, E. D., Age related reactivation of an X-linked gene. Nature327 (1987) 725–727.
Watt, F., and Molloy, P. L., Cytosine methylation prevents binding to DNA of a HeLa cell transcription factor required for optimal expression of the adenovirus major late promoter. Genes Devl.2 (1988) 1136–1143.
Weil, C. F., and Wessler, S. R., The effects of plant transposable element insertion on transcription initiation and RNA processing. A. Rev. Plant Physiol. Plant molec. Biol.41 (1990) 520–552.
Weisshaar, B., Langner, K.-D., Jüttermann, R., Müller, U., Zock, C., Klimkait, T., and Doerfler, W., Reactivation of the methylation inactivated late E2A promoter of adenovirus type 2 by E1A (13S) functions. J. molec. Biol.202 (1988) 255–270.
Wiebauer, K., and Jiricny, J., In vitro correction of G·T mispairs to G·C pairs in nuclear extracts from human cells. Nature339 (1989) 234–236.
Wiebauer, K., and Jiricny, J., Mismatch-specific thymine DNA glycosylase and DNA polymerase β mediate the correction of G·T mispairs in nuclear extracts from human cells. Proc. natl Acad. Sci.87 (1990) 5842–5845.
Wilke, K., Rauhut, E., Noyer-Weidner, M., Lauster, R., Pawlek, B., Behrens, B., and Trautner, T., Sequential order of target-recognizing domains in multispecific DNA-methyltransferases. EMBO J.7 (1988) 2601–2609.
Wilks, A., Seldran, M., and Jost, J.-P., An estrogen-dependent demethylation at the 5′ end of the chicken vitellogenin gene is independent of DNA synthesis. Nucl. Acids Res.12 (1984) 1163–1177.
Wilson, V. L., and Jones, P. A., DNA methylation decreases in aging but not in immortal cells. Science220 (1983) 1055–1057.
Woodcock, D. M., Crowther, P. J., and Diver, W. P., The majority of methylated deoxycytidines in human DNA are not in the CpG dinucleotide. Biochem. biophys. Res. Com.145 (1987) 888–894.
Wu, J. C., and Santi, D. V., Kinetic and catalytic mechanism of HhaI methyltransferase. J. biol. Chem.262 (1987) 4778–4786.
Yesufu, H. M. I., Hanley, A., Rinaldi, A., and Adams, R. L. P., DNA methylase fromPisum sativum. Biochem. J.273 (1991) 469–475.
Yisraeli, J., Adelstein, R. S., Melloul, D., Nudel, U., Yaffe, D., and Cedar, H., Muscle-specific activation of a methylated chimeric actin gene. Cell46 (1986) 409–416.
Young, P. R., and Tilghman, S. M., Induction of α-fetoprotein synthesis in differentiating F9 teratocarcinoma cells in accompanied by a genome-wide loss of DNA methylation. Molec. cell. Biol.4 (1984) 898–907.
Zhang, X.-Y., Asiedu, C. K., Supakar, P. C., Khan, R., Ehrlich, K. C., and Ehrlich, M., Binding sites in mammalian genes and viral gene regulatory regions recognized by methylated DNA-binding protein. Nucl. Acids Res.18 (1990) 6253–6260.
Zhu, X., Dunn, J. M., Phillips, R. A., Goddard, A. D., Paton, K. E., Becker, A., and Gallie, B. L., Preferential germline mutation of the paternal allele in retinoblastoma. Nature340 (1989) 312–313.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hergersberg, M. Biological aspects of cytosine methylation in eukaryotic cells. Experientia 47, 1171–1185 (1991). https://doi.org/10.1007/BF01918381
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF01918381