Abstract
This chapter presents a personal account of the work on DNA methylation in viral and mammalian systems performed in the author’s laboratory in the course of the past 30 years. The text does not attempt to give a complete and meticulous account of the work accomplished in many other laboratories; in that sense it is not a review of the field in a conventional sense. Since the author is also one of the editors of this series of Current Topics in Immunology and Microbiology on DNA methylation, to which contributions by many of our colleagues in this field have been invited, the author’s conscience is alleviated that he has not cited many of the relevant and excellent reports by others. The choice of viral model systems in molecular biology is well founded. Over many decades, viruses have proved their invaluable and pioneering role as tools in molecular genetics. When our interest turned to the demonstration of genome-wide patterns of DNA methylation, we focused mainly on the human genome. The following topics in DNA methylation will be treated in detail: (1) The de novo methylation of integrated foreign genomes; (2) the long-term gene silencing effect of sequence-specific promoter methylation and its reversal; (3) the properties and specificity of patterns of DNA methylation in the human genome and their possible relations to pathogenesis; (4) the long-range global effects on cellular DNA methylation and transcriptional profiles as a consequence of foreign DNA insertion into an established genome; (5) the patterns of DNA methylation can be considered part of a cellular defense mechanism against foreign or repetitive DNA; which role has food-ingested DNA played in the elaboration of this mechanism? The interest in problems related to DNA methylation has spread—like the mechanism itself—into many neighboring fields. The nature of the transcriptional programs orchestrating embryonal and fetal development, chromatin structure, genetic imprinting, genetic disease, X chromosome inactivation, and tumor biology are but a few of the areas of research that have incorporated studies on the importance of the hitherto somewhat neglected fifth nucleotide in many genomes. Even the fly researchers now have to cope with the presence of this nucleotide, in however small quantities it exists in the genome of their model organism, at least during embryonal development. The bulk of the experimental work accomplished in the author’s laboratory has been shouldered by many very motivated undergraduate and graduate students and by a number of talented postdoctoral researchers. Their contributions are reflected in the list of references in this chapter. We have also had the good luck to receive funding through a number or organizations as acknowledged.
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References
Achten A, Behn-Krappa A, Jücker M, Sprengel J, Hölker I, Schmitz B, Tesch H, Diehl V, Doerfler W (1991) Patterns of DNA methylation in selected human genes in different Hodgkin’s lymphoma and leukemia cell lines and in normal human lymphocytes. Cancer Res 51:3702–3709
Badal S, Badal V, Calleja-Maicas IE, Kalantari M, Chuang LS, Li BF, Bernard HU (2004) The human papillomavirus-18 genome is efficiently targeted by cellular DNA methyltransferases. Virology 324:483–492
Beck S, Olek A (eds) (2003) The epigenome. Wiley-VCH, Weinheim
Behn-Krappa A, Doerfler W (1993) The state of DNA methylation in the promoter and exon 1 regions of the human gene for the interleukin-2 receptor α chain (IL-2Rα) in various cell types. Hum Mol Genet 2:993–999
Behn-Krappa A, Hölker I, Sandaradura de Silva U, Doerfler W (1991) Patterns of DNA metyhlation are indistinguishable in different individuals over a wide range of human DNA sequences. Genomics 11:1–7
Bestor TH (1998) The host defence function of genomic methylation patterns. Novartis Found Symp 241:187–199
Church GM, Gilbert W (1984) Genomic sequencing. Proc Natl Acad Sci USA 81:1991–1995
Clark SJ, Harrison J, Paul CL, Frommer M (1994) High sensitivity mapping of methylated cytosines. Nucleic Acids Res 22:2990–2997
Conklin KF, Coffin JM, Robinson HL, Groudine M, Eisenman R (1982) Role of methylation in the induced and spontaneous expression of the avian endogenous virus ev-1: DNA structure and gene products. Mol Cell Biol 2:638–652
Cook JL, Lewis AM Jr (1979) Host response to adenovirus 2-transformed hamster embryo cells. Cancer Res 39:1455–1461
Deissler H, Behn-Krappa A, Doerfler W (1996) Purification of nuclear proteins from human HeLa cells that bind specifically to the unstable tandem repeat (CGG)n in the human FMR1 gene. J Biol Chem 271:4327–4334
Deissler H, Wilm M, Genç B, Schmitz B, Ternes T, Naumann F, Mann M, Doerfler W (1997) Rapid protein sequencing by tandem mass spectrometry and cDNA cloning of p20-CGGBP. J Biol Chem 272:16761–16768
Desrosiers RC, Mulder C, Fleckenstein B (1979) Methylation of herpesvirus saimiri DNA in lymphoid tumor cell lines. Proc Natl Acad Sci USA 76:3839–3843
Deuring R, Doerfler W (1983) Proof of recombination between viral and cellular genomes in human KB cells productively infected by adenovirus type12: structure of the junction site in a symmetric recombinant (SYREC). Gene 26:283–289
Deuring R, Klotz G, Doerfler W (1981) An unusual symmetric recombinant between adenovirus type 12 DNA and human cell DNA. Proc Natl Acad Sci USA 78:3142–3146
Dobrzanski P, Hoeveler A, Doerfler W (1988) Inactivation by sequence-specific methylations of adenovirus promoters in a cell-free system. J Virol 62:3941–3946
Doerfler W (1968) The fate of the DNA of adenovirus type 12 in baby hamster kidney cells. Proc Natl Acad Sci USA 60:636–643
Doerfler W (1969) Nonproductive infection of baby hamster kidney cells (BHK21) with adenovirus type 12. Virology 38:587–606
Doerfler W (1970) Integration of the deoxyribonucleic acid of adenovirus type 12 into the deoxyribonucleic acid of baby hamster kidney cells. J Virol 6:652–666
Doerfler W (1981) DNA methylation—a regulatory signal in eukaryotic gene expression. J Gen Virol 57:1–20
Doerfler W (1982) Uptake, fixation, and expression of foreign DNA in mammalian cells: the organization of integrated adenovirus DNA sequences. Curr Top Microbiol Immunol 101:127–194
Doerfler W (1983) DNA methylation and gene activity. Annu Rev Biochem 52:93–124
Doerfler W (1991a) Abortive infection and malignant transformation by adenoviruses: integration of viral DNA and control of viral gene expression by specific patterns of DNA methylation. Adv Virus Res 39:89–128
Doerfler W (1991b) Patterns of DNA methylation—evolutionary vestiges of foreign DNA inactivation as a host defense mechanism—a proposal. Biol Chem Hoppe Seyler 372:557–564
Doerfler W (1995) The insertion of foreign DNA into mammalian genomes and its consequences: a concept in oncogenesis. Adv Cancer Res 66:313–344
Doerfler W (1996) A new concept in (adenoviral) oncogenesis: integration of foreign DNA and its consequences. Biochim Biophys Acta 1288:F79–F99
Doerfler W (2000) Foreign DNA in mammalian systems. Wiley-VCH, Weinheim
Doerfler W, Kruczek I, Eick D, Vardimon L, Kron B (1982) DNA methylation and gene activity: the adenovirus system as a model. Cold Spring Harb Symp Quant Biol 47:593–603
Doerfler W, Gahlmann R, Stabel S, Deuring R, Lichtenberg U, Schulz M, Eick D, Leisten R (1983) On the mechanism of recombination between adenoviral and cellular DNAs: the structure of junction sites. Curr Top Microbiol Immunol 109:193–228
Doerfler W, Weisshaar B, Hoeveler A, Knebel D, Müller U, Dobrzanski P, Lichtenberg U, Achten S, Herrman R (1988) Promoter inhibitionby DNA methylation: a reversible signal. Gene 74:129–133
Doerfler W, Hohlweg U, Müller K, Remus R, Heller H, Hertz J (2001) Foreign DNA integration—perturbations of the genome—oncogenesis. Ann N Y Acad Sci 945:276–288
Eick D, Doerfler W (1982) Integrated adenovirus type 12 DNA in the transformed hamster cell line T637: sequence arrangements at the termini of viral DNA and mode of amplification. J Virol 42:317–321
Eick D, Stabel S, Doerfler W (1980) Revertants of adenovirus type 12-transformed hamster cell line T637 as tools in the analysis of integration patterns. J Virol 36:41–49
Engler P, Haasch D, Pinkert CA, Doglio L, Glymour M, Brinster R, Storb U (1991) A strain-specific modifier on mouse chromosome 4 controls the methylation of independent transgene loci. Cell 65:939–947
Ernberg I, Falk K, Minarovits J, Busson P, Tursz T, Masucci MG, Klein G (1989) The role of methylation in the phenotype-dependent modulation of Epstein-Barr nuclear antigen 2 and latent membrane protein genes in cells latently infected with Epstein-Barr virus. J gen Virol 70:2989–3002
Flint J, Shenk T (1989) Adenovirus E1A protein paradigm viral transactivator. Annu Rev Genet 23:141–161
Frommer M, McDonald LE, Millar DS, Collis CM, Watt F, Grigg GW, Molloy PL, Paul CL (1992) A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proc Natl Acad Sci USA 89:1827–1831
Genç B, Müller-Hartmann H, Zeschnigk M, Deissler H, Schmitz B, Majewski F, von Gontard A, Doerfler W (2000) Methylation mosaicism of 5′-(CGG)n-3′ repeats in fragile X, premutation and healthy individuals. Nucleic Acids Res 28:2141–2152
Groneberg J, Sutter D, Soboll H, Doerfler W (1978)Morphological revertants of adenovirus type 12-transformed hamster cells. J gen Virol 40:635–645
Günthert U, Schweiger M, Stupp M, Doerfler W (1976) DNA methylation in adenovirus, adenovirus-transformed cells, and host cells. Proc Natl Acad Sci USA 73:3923–3927
Hacein-Bey-Abina S, von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, Lim A, Osborne CS, Pawliuk R, Morillon E, et al (2003) LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302:415–419
Heller H, Kämmer C, Wilgenbus P, Doerfler W (1995) Chromosomal insertion of foreign (adenovirus type 12, plasmid, or bacteriophage lambda) DNA is associated with enhanced methylation of cellular DNA segments. Proc Natl Acad Sci USA 92:5515–5519
Hermann R, Doerfler W (1991) Interference with protein binding at AP2 sites by sequence-specific methylation in the late E2A promoter of adenovirus type 2 DNA. FEBS Lett 281:191–195
Hermann R, Hoeveler A, Doerfler W (1989) Sequence-specific methylation in a down-stream region of the late E2A promoter of adenovirus type 2DNA prevents protein binding. J Mol Biol 210:411–415
Hertz J, Schell G, Doerfler W (1999) Factors affecting de novo methylation of foreign DNA in mouse embryonic stem cells. J Biol Chem 274:24232–24240
Hilger-Eversheim K, Doerfler W (1997) Clonal origin of adenovirus type 12-induced hamster tumors: nonspecific chromosomal integration sites of viral DNA. Cancer Res 57:3001–3009
Hohlweg U, Doerfler W (2001) On the fate of plant or other foreign genes upon the uptake in food or after intramuscular injection in mice. Mol Genet Genomics 265:225–233
Hohlweg U, Hösel M, Dorn A, Webb D, Hilger-Eversheim K, Remus R, Schmitz B, Mende Y, Buettner R, Schramme A, Corzilius L, Niemann A, Doerfler W (2003) Intraperitoneal dissemination of Ad12-induced undifferentiated neuroectodermal hamster tumors: de novo methylation and transcription patterns of integrated viral and of cellular genes. Virus Res 98:45–56
Hösel M, Webb D, Schröer J, Schmitz B, Doerfler W (2001) The overexpression of the adenovirus type 12 pTP or E1A gene facilitates Ad12 DNA replication in non-permissive BHK21 hamster cells. J Virol 75:16041–16053
Hotchkiss RD (1948) The quantitative separation of purines, pyrimidines, and nucleosides by paper chromatography. J Biol Chem 175:315–332
Jähner D, Stuhlman H, Stewart CL, Harbers K, Lohler J, Simon I, Jaenisch R (1982) De novo methylation and expression of retroviral genomes during mouse embryogenesis. Nature 298:623–628
Johansson K, Persson H, Lewis AM, Pettersson U, Tibbetts C, Philipson L (1978) Viral DNA sequences and gene products in hamster cells transformed by adenovirus type 2. J Virol 27:628–639
Kämmer C, Doerfler W (1995) Genomic sequencing reveals absence of DNA methylation in the major late promoter of adenovirus type 2 DNA in the virion and in productively infected cells. FEBS Lett 362:301–305
Karlin S, Doerfler W, Cardon LR (1994) Why is CpG suppressed in the genomes of virtually all small eukaryotic viruses but not in those of large eukaryotic viruses? J Virol 68:2889–2897
Knebel D, Doerfler W (1986) N6-Methyldeoxyadenosine residues at specific sites decrease the activity of the E1A promoter of adenovirus type 12 DNA. J Mol Biol 189:371–375
Knebel D, Lübbert H, Doerfler W (1985) The promoter of the late p10 gene in the insect nuclear polyhedrosis virus Autographa californica: activation by viral gene products and sensitivity to DNA methylation. EMBO J 4:1301–1306
Knebel-Mörsdorf D, Achten S, Langner KD, Rüger R, Fleckenstein B, Doerfler W (1988) Reactivation of the methylation-inhibited late E2A promoter of adenovirus type 2 by a strong enhancer of human cytomegalovirus. Virology 166:166–174
Knoblauch M, Schröer J, Schmitz B, Doerfler W (1996) The structure of adenovirus type 12 DNA integration sites in the hamster cell genome. J Virol 70:3788–3796
Knust B, Brüggemann U, Doerfler W (1989) Reactivation of a methylation-silenced gene in adenovirus-transformed cells by 5-azacytidine or by E1A trans activation. J Virol 63:3519–3524
Kochanek S, Toth M, Dehmel A, Renz D, Doerfler W (1990) Interindividual concordance of methylation profiles in human genes for tumor necrosis factors α and β. Proc Natl Acad Sci USA 87:8830–8834
Kochanek S, Radbruch A, Tesch H, Renz D, Doerfler W (1991) DNA methylation profiles in the human genes for tumor necrosis factors α and β in subpopulations of leukocytes and in leukemias. Proc Natl Acad Sci USA 88:5759–5763
Kochanek S, Renz D, Doerfler W (1993) DNA methylation in the Alu sequences of diploid and haploid primary human cells. EMBO J 12:1141–1151
Kochanek S, Renz D, Doerfler W (1995) Transcriptional silencing of human Alu sequences and inhibition of protein binding in the box B regulatory elements by 5′-CG-3′ methylation. FEBS Lett 360:115–120
Kochanek S, Hosokawa K, Schiedner G, Renz D, Doerfler W (1996a) DNA methylation in the promoter of ribosomal RNA genes in human cells as determined by genomic sequencing. FEBS Lett 388:192–194
Kochanek S, Clemens PR, Mitani K, Chen HH, Chan S, Caskey CT (1996b) A new adenoviral vector: replacement of all viral coding sequences with 28 kb of DNA independently expressing both full-length dystrophin and beta-galactosidase. Proc Natl Acad Sci USA 93:5731–5736
Koetsier PA, Mangel L, Schmitz B, Doerfler W (1996) Stability of transgene methylation patterns in mice: position effects, strain specificity and cellular mosaicism. Transgenic Res 5:235–244
Kruczek I, Doerfler W (1982) The unmethylated state of the promoter/leader and 5′-regions of integrated adenovirus genes correlates with gene expression. EMBO J 1:409–414
Kruczek I, Doerfler W (1983) Expression of the chloramphenicol acetyltransferase gene in mammalian cells under the control of adenovirus type 12 promoters: effect of promoter methylation on gene expression. Proc Natl Acad Sci USA 80:7586–7590
Kuff EL, Fewell JE, Lueders KK, DiPaolo JA, Amsbaugh SC, Popescu NC (1986) Chromosome distribution of intracisternal A-particle sequences in the Syrian hamster and mouse. Chromosoma 93:213–219
Kuhlmann I, Doerfler W (1982) Shifts in the extent and patterns of DNA methylation upon explantation and subcultivation of adenovirus type 12-induced hamster tumor cells. Virology 118:169–180
Kuhlmann I, Achten S, Rudolph R, Doerfler W (1982) Tumor induction by human adenovirus type 12 in hamsters: loss of the viral genome from adenovirus type 12-induced tumor cells is compatible with tumor formation. EMBO J 1:79–86
Langner KD, Vardimon L, Renz D, Doerfler W (1984) DNAmethylation of three 5′ C-CG-G 3′ sites in the promoter and 5′ region inactivates the E2a gene of adenovirus type 2. Proc Natl Acad Sci USA 81:2950–2954
Langner KD, Weyer U, Doerfler W (1986) Trans effect of the E1 region of adenoviruses on the expression of a prokaryotic gene in mammalian cells: resistance to 5′-CCGG-3′ methylation. Proc Natl Acad Sci USA 83:1598–1602
Lettmann C, Schmitz B, Doerfler W (1991) Persistence or loss of preimposed methylation patterns and de novo methylation of foreign DNA integrated in transgenic mice. Nucleic Acids Res 19:7131–7137
Lichtenberg U, Zock C, Doerfler W (1987) Insertion of adenovirus type 12 DNA in the vicinity of an intracisternal A particle genome in Syrian hamster tumor cells. J Virol 61:2719–2726
Lichtenberg U, Zock C, Doerfler W (1988) Integration of foreign DNA into mammalian genome can be associated with hypomethylation at site of insertion. Virus Res 11:335–342
Lueders KK, Kuff EL (1981) Sequences homologous to retrovirus-like genes of the mouse are present in multiple copies in the Syrian hamster genome. Nucleic Acids Res 9:5917–5930
McClelland M, Nelson M (1988) The effect of site-specific methylation on restriction endonucleases and DNA modification methyltransferases—a review. Gene 74:291–304
Meyer P (ed) (1995) Gene silencing in higher plants and related phenomena in other eukaryotes. Curr Top Microbiol Immunol 197
Meyer zu Altenschildesche G, Heller H, Wilgenbus P, Tjia ST, Doerfler W (1996) Chromosomal distribution of the hamster intracisternal A-particle (IAP) retrotransposons. Chromosoma 104:341–344
Muiznieks I, Doerfler W (1994a) The impact of 5′-CG-3′ methylation on the activity of different eukaryotic promoters: a comparative study. FEBS Lett 344:251–254
Muiznieks I, Doerfler W (1994b) The topology of the promoter of RNA polymerase II-and III-transcribed genes is modified by the methylation of 5′-CG-3′ dinucleotides. Nucleic Acids Res 22:2568–2575
Muiznieks I, Doerfler W (1998) DNA fragments with specific nucleotide sequences in their single-stranded termini exhibit unusual electrophoretic mobilities. Nucleic Acids Res 26:1899–1905
Müller K, Heller H, Doerfler W (2001) Foreign DNA integration: genome-wide perturbations of methylation and transcription in the recipient genomes. J Biol Chem 276:14271–14278
Müller U, Doerfler W (1987) Fixation of unmethylated or the 5′-CCGG-3′ methylated adenovirus late E2A promoter-cat gene construct in the genome of hamster cells: gene expression and stability of methylation patterns. J Virol 61:3710–3720
Müller-Hartmann H, Deissler H, Naumann F, Schmitz B, Doerfler W (2000) The human 20-kDa 5′-(CGG)n-3′-binding protein is targeted to the nucleus and affects the activity of the FMR1 promoter. J Biol Chem 275:6447–6452
Munnes M, Doerfler W (1997) DNA methylation in mammalian genomes: promoter activity and genetic imprinting. In: Dulbecco R (ed) Encyclopedia of human biology, vol. 3. Academic Press, San Diego, pp 435–446
Munnes M, Schetter C, Hölker I, Doerfler W (1995) A fully 5′-CG-3′ but not a 5′-CCGG-3′ methylated late frog virus 3 promoter retains activity. J Virol 69:2240–2247
Munnes M, Patrone G, Schmitz B, Romeo G, Doerfler W (1998) A 5′-CG-3′-rich region in the promoter of the transcriptionally frequently silenced RET protooncogene lacks methylated cytidine residues. Oncogene 17:2573–2584
Naumann F, Remus R, Schmitz B, Doerfler W (2004) Gene structure and expression of the 5′-(CGG)n-3′-binding protein (CGGBP1). Genomics 83:108–120
Nevins JR (1995) Adenovirus E1A: transcription regulation and alteration of cell growth control. Curr Top Microbiol Immunol 199/III:25–32
Ono M, Ohishi H (1983) Long terminal repeat sequences of intracisternal A particle genes in the Syrian hamster genome: identification of tRNAPhe as a putative primer tRNA. Nucleic Acids Res 11:7169–7179
Orend G, Kuhlmann I, Doerfler W (1991) Spreading of DNA methylation across integrated foreign (adenovirus type 12) genomes in mammalian cells. J Virol 65:4301–4308
Orend G, Linkwitz A, Doerfler W (1994) Selective sites of adenovirus (foreign) DNA integration into the hamster genome: changes in integration patterns. J Virol 68:187–194
Orend G, Knoblauch M, Kämmer C, Tjia ST, Schmitz B, Linkwitz A, Meyer zu Altenschildesche G, Maas J, Doerfler W (1995a) The initiation of de novo methylation of foreign DNA integrated into a mammalian genome is not exclusively targeted by nucleotide sequence. J Virol 69:1226–1242
Orend G, Knoblauch M, Doerfler W (1995b) Selective loss of unmethylated segments of integrated Ad12 genomes in revertants of the adenovirus type 12-transformed cell line T637. Virus Res 38:261–267
Ortin J, Scheidtmann KH, Greenberg R, Westphal M, Doerfler W (1976) Transcription of the genome of adenovirus type 12. III. Maps of stable RNA from productively infected human cells and abortively infected and transformed hamster cells. J Virol 20:355–372
Palka-Santini M, Schwarz-Herzke B, Brondke H, Renz D, Schmitz B, Auerochs S, Doerfler W (2003) The gastrointestinal tract as the portal of entry for foreign macromolecules: fate of DNA and protein. Mol Genet Genomics 270:201–215
Passarge E (2002) Gastrointestinal tract and hepatobiliar duct system. In: Rimoin DL, Connor JM, Pyeritz RE, Korf BR (eds) Principles and practice of medical genetics, 4th edn. Churchill Livingstone, London, pp 1747–1759
Pfeffer A, Schubbert R, Orend G, Hilger-Eversheim K, Doerfler W (1999) Integrated viral genomes can be lost from adenovirus type 12-induced hamster tumor cells in a clone-specific, multistep process with retention of the oncogenic phenotype. Virus Res 59:113–127
Rakyan VK, Hildmann T, Novik KL, Lewin J, Tost J, Cox AV, Andrews TD, Howe KL, Otto T, Olek A, Fischer J, Gut IG, Berlin K, Beck S (2004) DNA methylation profiling of the human major histocompatibility complex: a pilot study for the human epigenome project. PloS Biol 2:e405
Reik W, Howlett SK, Surani MA (1990) Imprinting of DNA methylation: from transgenes to endogenous gene sequences. Development Suppl 99–106
Remus R, Kämmer C, Heller H, Schmitz B, Schell G, Doerfler W (1999) Insertion of foreign DNA into an established mammalian genome can alter the methylation of cellular DNA sequences. J Virol 73:1010–1022
Remus R, Zeschnigk M, Zuther I, Kanzaki A, Wada H, Yawata A, Muiznieks I, Schmitz B, Schell G, Yawata Y, Doerfler W (2001) The state of DNA methylation in promoter regions of the human red cell membrane protein (band 3, protein 4.2 and β-spectrin) genes. Gene Funct Dis 2:171–184
Remus R, Kanzaki A, Nakanishi H, Wada H, Yawata A, Muiznieks I, Zeschnigk M, Zuther I, Muiznieks I, Schmitz B, Doerfler W, Yawata Y (2005) DNA methylation in promoter regions of red cell membrane protein genes in normal individuals and hereditary membrane disorders. Int J Hematol 81:385–395
Remus R, Kanzaki A, Yawata A, Nakanishi H, Wada H, Sugihara T, Zeschnigk M, Zuther I, Schmitz B, Naumann F, Yawata Y, Doerfler W (2005) Relations between DNA methylation and expression in erythrocyte membrane genes (band3, 4.2, and spectrin) during human erythroid differentiation. Int J Hematol (in press)
Sapienza C, Paquette J, Tran TH, Peterson A (1989) Epigenetic and genetic factors affect transgene methylation imprinting. Development 107:165–168
Schetter C, Grünemann B, Hölker I, Doerfler W (1993) Patterns of frog virus 3 DNA methylation and DNA methyltransferase activity in nuclei of infected cells. J Virol 67:6973–6978
Schiedner G, Schmitz B, Doerfler W (1994) Late transcripts of adenovirus type 12 DNA are not translated in hamster cells expressing the E1 region of adenovirus type 5. J Virol 68:5476–5482
Schröer J, Hölker I, Doerfler W (1997) Adenovirus type 12 DNA firmly associates with mammalian chromosomes early after virus infection or after DNA transfer by the addition of DNA to the cell culture medium. J Virol 71:7923–7932
Schubbert R, Lettmann C, Doerfler W (1994) Ingested foreign (phage M13) DNA survives transiently in the gastrointestinal tract and enters the bloodstream of mice. Mol Gen Genet 242:495–504
Schubbert R, Renz D, Schmitz B, Doerfler W (1997) Foreign (M13) DNA ingested by mice reaches peripheral leukocytes, spleen and liver via the intestinal wall mucosa and can be covalently linked to mouse DNA. Proc Natl Acad Sci USA 94:961–966
Schubbert R, Hohlweg U, Doerfler W (1998) On the fate of food-ingested foreign DNA in mice: chromosomal association and placental transmission to the fetus. Mol Gen Genet 259:569–576
Schumacher A, Doerfler W (2004) Influence of in vitro manipulation on the stability of methylation patterns in the Snurf/Snrpn-imprinting region in mouse embryonic stem cells. Nucleic Acids Res 32:1566–1576
Schumacher A, Buiting K, Zeschnigk M, Doerfler W, Horsthemke B (1998) Methylation analysis of the PWS/AS region does not support an enhancer competition model of genomic imprinting on human chromosome 15. Nat Genet 19:324–325
Schumacher A, Koetsier PA, Hertz JM, Doerfler W (2000) Epigenetic and genotypespecific effects on the stability of de novo imposed methylation patterns in transgenic mice. J Biol Chem 275:37915–37921
Schumacher A, Arnhold S, Addicks K, Doerfler W (2003) Staurosporine is a potent activator of neuronal, glial, and “CNS stem cell”-like neurosphere differentiation in murine embryonic stem cells. Mol Cell Neurosci 23:669–680
Schwemmle S, de Graaff E, Deissler H, Gläser D, Wöhrle D, Kennerknecht I, Just W, Oostra BA, Doerfler W, Vogel W, Steinbach P (1997) Characterization of FMR1 promoter elements by in vivo-footprinting analysis. Am J Hum Genet 60:1354–1362
Southern EM (1975) Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol 98:503–517
Sprengel J, Schmitz B, Heuss-Neitzel D, Zock C, Doerfler W (1994) Nucleotide sequence of human adenovirus type 12 DNA: comparative functional analysis. J Virol 68:379–389
Stabel S, Doerfler W, Friis RR (1980) Integration sites of adenovirus type 12 DNA in transformed hamster cells and hamster tumor cells. J Virol 36:22–40
Strohl WA, Rabson AS, Rouse H (1967) Adenovirus tumorigenesis: role of the viral genome in determining tumor morphology. Science 156:1631–1633
Sutherland GR, Gecz J, Mulley JC (2002) Fragile X syndrome and other causes of X-linked mental handicap. In: Rimoin DL, Connor JM, Pyeritz RE, Korf BR (eds) Principles and practice of medical genetics, 4th edn. Churchill Livingstone, London, pp 2801–2826
Sutter D, Doerfler W (1979) Methylation of integrated viral DNA sequences in hamster cells transformed by adenovirus 12. Cold Spring Harb Symp Quant Biol 44:565–568
Sutter D, Doerfler W (1980) Methylation of integrated adenovirus type 12 DNA sequences in transformed cells is inversely correlated with viral gene expression. Proc Natl Acad Sci USA 77:253–256
Sutter D, Westphal M, Doerfler W (1978) Patterns of integration of viral DNA sequences in the genomes of adenovirus type 12-transformed hamster cells. Cell 14:569–585
Thompson JP, Granoff A, Willis DB (1988) Methylation of the promoter of an immediate-early frog virus 3 gene does not inhibit transcription. J Virol 62:4680–4685
Toth M, Lichtenberg U, Doerfler W (1989) Genomic sequencing reveals a 5-methylcytosine-free domain in active promoters and the spreading of preimposed methylation patterns. Proc Natl Acad Sci USA 86:3728–3732
Toth M, Müller U, Doerfler W (1990) Establishment of de novo DNA methylation patterns. Transcription factor binding and deoxycytidine methylation at CpG and non-CpG sequences in an integrated adenovirus promoter. JMol Biol 214:673–683
Ushijima T, Morimura K, Hosoya Y, Okonogi H, Tatematsu M, Sugimura T, Nagao M (1997) Establishment of methylation-sensitive representational difference analysis and isolation of hypo-and hypermethylated genomic fragments in mouse liver tumors. Proc Natl Acad Sci USA 94:2103–2105
Vardimon L, Neumann R, Kuhlmann I, Sutter D, Doerfler W (1980) DNA methylation and viral gene expression in adenovirus-transformed and-infected cells. Nucleic Acids Res 8:2461–2473
Vardimon L, Kuhlmann I, Doerfler W, Cedar H (1981) Methylation of adenovirus genes in transformed cells and in vitro: influence on the regulation of gene expression? Eur J Cell Biol 25:13–15
Vardimon L, Kressmann A, Cedar H, Maechler M, Doerfler W (1982a) Expression of a cloned adenovirus gene is inhibited by in vitro methylation. Proc Natl Acad Sci USA 79:1073–1077
Vardimon L, Günthert U, Doerfler W (1982b) In vitro methylation of the BsuRI (5′-GGCC-3′) sites in the E2a region of adenovirus type 2 DNA does not affect expression in Xenopus laevis oocytes. Mol Cell Biol 2:1574–1580
Waalwijk C, Flavell RA (1978) MspI, an isoschizomer of HpaII which cleaves both unmethylated and methylated HpaII sites. Nucleic Acids Res 5:3231–3236
Weisshaar B, Langner KD, Jüttermann R, Müller U, Zock C, Klimkait T, Doerfler W (1988) Reactivation of the methylation-inactivated late E2A promoter of adenovirus type 2 by E1A (13S) functions. J Mol Biol 202:255–270
Wienhues U, Doerfler W (1985) Lack of evidence for methylation of parental and newly synthesized adenovirus type 2 DNA in productive infections. J Virol 56:320–324
Willis DB, Granoff A (1980) Frog virus 3 DNA is heavily methylated at CpG sequences. Virology 107:250–257
Woodcock DM, Crowther PJ, Jefferson S, Diver WP (1988) Methylation at dinucleotides other than CpG: implications for human maintenance methylation. Gene 74:151–152
Yawata Y (2003) Cell membrane. Wiley-VCH, Weinheim
Yoder JA, Walsh CP, Bestor TH (1997) Cytosine methylation and the ecology of intragenomic parasites. Trends Genet 13:335–340
Zantema A, van der Eb AJ (1995) Modulation of gene expression by adenovirus transformation. Curr Top Microbiol Immunol 199:1–23
Zeschnigk M, Schmitz B, Dittrich B, Buiting K, Horsthemke B, Doerfler W (1997a) Imprinted segments in the human genome: different DNA methylation patterns in the Prader-Willi/Angelman syndrome region as determined by the genomic sequencing method. Hum Mol Genet 6:387–395
Zeschnigk M, Lich C, Buiting K, Doerfler W, Horsthemke B (1997b) A single-tube PCR test for the diagnosis of Angelman and Prader-Willi syndrome based on allelic methylation differences at the SNRPN locus. Eur J Hum Genet 5:94–98
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Doerfler, W. (2006). De Novo Methylation, Long-Term Promoter Silencing, Methylation Patterns in the Human Genome, and Consequences of Foreign DNA Insertion. In: Doerfler, W., Böhm, P. (eds) DNA Methylation: Basic Mechanisms. Current Topics in Microbiology and Immunology, vol 301. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-31390-7_5
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