Chromosomal insertion of foreign (adenovirus type 12, plasmid, or bacteriophage lambda) DNA is associated with enhanced methylation of cellular DNA segments.

Heller, Hilde; Kämmer, Christina; Wilgenbus, Petra; Doerfler, Walter

doi:10.1073/pnas.92.12.5515

Cited by 113 publications

(126 citation statements)

References 27 publications

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“…Similar changes were documented in cells carrying bacterial plasmid or bacteriophage λ DNA as foreign genome inserts [5,6]. As a corollary, transcriptional profiles in Ad12 DNA or λ DNA transgenomic hamster cell genomes were significantly altered [7].…”

supporting

confidence: 49%

“…This study extends earlier work on changes of cellular transcription and methylation patterns in mammalian cells upon the chromosomal insertion of viral or plasmid DNAs [5][6][7]16]. We have now chosen a targeted approach and used human cells in culture with a small integrated bacterial plasmid (pC1-5.6), which carried the kanamycin gene under SV40 promoter control.…”

Section: Resultsmentioning

confidence: 56%

“…Studies on mammalian cells with integrated viral (adenovirus type 12, Ad12) DNA [1][2][3][4] revealed that cellular genomes as foreign DNA recipients exhibited genomewide alterations of DNA methylation patterns [5]. Similar changes were documented in cells carrying bacterial plasmid or bacteriophage λ DNA as foreign genome inserts [5,6].…”

mentioning

confidence: 88%

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Destabilization of the Human Epigenome: Consequences of Foreign DNA Insertions

et al. 2015

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Aim: We previously reported changes of DNA methylation and transcription patterns in mammalian cells that carry integrated foreign DNA. Experiments were now designed to assess the epigenetic consequences of inserting a 5.6 kbp plasmid into the human genome. Methods: Differential transcription and CpG methylation patterns were compared between transgenomic and nontransgenomic cell clones by using gene chip microarray systems. Results: In 4.7% of the 28.869 gene segments analyzed, transcriptional activities were up- or downregulated in the transgenomic cell clones. Genome-wide profiling revealed differential methylation in 3791 of > 480,000 CpG's examined in transgenomic versus nontransgenomic clones. Conclusion: The data document genome-wide effects of foreign DNA insertions on the epigenetic stability of human cells. Many fields in experimental biology and medicine employ transgenomic or otherwise genome-manipulated cells or organisms without considering the epigenetic consequences for the recipient genomes.

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supporting

confidence: 49%

Section: Resultsmentioning

confidence: 56%

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Destabilization of the Human Epigenome: Consequences of Foreign DNA Insertions

et al. 2015

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“…During hepatocarcinogenesis, in addition to overexpression of the DNA methyltransferase, other mechanisms, such as integration of hepatitis B virus, may contribute to regional DNA hypermethylation: hepatitis B virus DNA is integrated in the cellular genome 55 and the integrated viral DNA is known to alter the DNA methylation status of several adjacent cellular genes and DNA segments. 56 The mRNA expression level of DNMT2 also showed no significant association with CIMP in HCCs. DNMT2 may strictly target specific recognition sequences, as do bacterial DNA methyltransferases, which show structural similarity to human DNMT2.…”

Section: Discussionmentioning

confidence: 99%

Expression of mRNA for DNA methyltransferases and methyl-CpG–binding proteins and DNA methylation status on CpG islands and pericentromeric satellite regions during human hepatocarcinogenesis

2001

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To evaluate the significance of alterations in DNA methylation during human hepatocarcinogenesis, we examined levels of mRNA for DNA methyltransferases and methylCpG-binding proteins and the DNA methylation status in 67 hepatocellular carcinomas (HCCs). The average level of mRNA for DNMT1 and DNMT3a was significantly higher in noncancerous liver tissues showing chronic hepatitis or cirrhosis than in histologically normal liver tissues, and was even higher in HCCs. Significant overexpression of DNMT3b and reduced expression of DNMT2 were observed in HCCs compared with the corresponding noncancerous liver tissues. DNA hypermethylation on CpG islands of the p16 (8% and 66%) and hMLH1 (0% and 0%) genes and methylated in tumor (MINT) 1 (6% and 34%), 2 (24% and 58%), 12 (21% and 33%), 25 (0% and 5%), and 31 (0% and 23%) clones, and DNA hypomethylation on satellites 2 and 3 (18% and 67%), were detected in noncancerous liver tissues and HCCs, respectively. There was no significant correlation between the expression level of any DNA methyltransferase and DNA methylation status. Reduced expression of DNA repair protein, MBD4, was significantly correlated with poorer tumor differentiation and involvement of portal vein. Slightly reduced expression of MBD2 was detected in HCCs, and the expression of MeCP2 was particularly reduced in HCCs with portal vein involvement. These data suggest that overexpression of DNMT1 and DNMT3a, DNA hypermethylation on CpG islands, and DNA hypomethylation on pericentromeric satellite regions are early events during hepatocarci- Aberrant DNA cytosine methylation is one of the most consistent epigenetic changes in human cancers. 1 Generally, the overall DNA methylation level is lower in cancer cells than in normal cells. 2 However, some loci tend to show increased DNA methylation in cancer cells, 3-6 whereas others are often hypomethylated in human cancers. 7 DNA methylation may play roles in carcinogenesis by virtue of 3 mechanisms: 1) DNA cytosine methylation facilitates gene mutation, as 5-methylcytosine is deaminated to thymine 8 ; 2) aberrant DNA methylation may be associated with allelic loss 3-7,9-11 ; and 3) DNA methylation occurs frequently in CpG islands near regulatory regions of genes and affects the transcription of specific genes. 1,12,13 Recently, 2 types of DNA methylation were described; methylation of CpG islands in a cancer-specific manner (type C methylation) differs from age-dependent methylation (type A methylation). 14 CpG islands of the p16 and hMLH1 genes and the methylated in tumor (MINT) 1, 2, 12, 25, and 31 clones show type C methylation, 14 although the genes whose expression were regulated by MINT clones were not identified. A high level of type C methylation in human cancer has been referred to as the CpG island methylator phenotype (CIMP). 14,15 With respect to hepatocarcinogenesis, we reported previously that aberrant DNA methylation on chromosome 16, a hot spot for loss of heterozygosity (LOH) in hepatocellular carcinomas (HCCs), is observed frequently in chroni...

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“…64 Aside from physical rearrangements, illegitimate DNA integration can alter other cellular characteristics, such as perturbation of genome-wide methylation patterns. 65,66 The mechanisms involved are not fully understood, but the consequences for the recipient genome can be drastic. Since gene expression levels can be modified by promoter methylation, 67 the integration of foreign DNA can give rise to diverse phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Illegitimate DNA integration in mammalian cells

2003

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Foreign DNA integration is one of the most widely exploited cellular processes in molecular biology. Its technical use permits us to alter a cellular genome by incorporating a fragment of foreign DNA into the chromosomal DNA. This process employs the cell's own endogenous DNA modification and repair machinery. Two main classes of integration mechanisms exist: those that draw on sequence similarity between the foreign and genomic sequences to carry out homology-directed modifications, and the nonhomologous or 'illegitimate' insertion of foreign DNA into the genome. Gene therapy procedures can result in illegitimate integration of introduced sequences and thus pose a risk of unforeseeable genomic alterations. The choice of insertion site, the degree to which the foreign DNA and endogenous locus are modified before or during integration, and the resulting impact on structure, expression, and stability of the genome are all factors of illegitimate DNA integration that must be considered, in particular when designing genetic therapies.

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Chromosomal insertion of foreign (adenovirus type 12, plasmid, or bacteriophage lambda) DNA is associated with enhanced methylation of cellular DNA segments.

Cited by 113 publications

References 27 publications

Destabilization of the Human Epigenome: Consequences of Foreign DNA Insertions

Destabilization of the Human Epigenome: Consequences of Foreign DNA Insertions

Expression of mRNA for DNA methyltransferases and methyl-CpG–binding proteins and DNA methylation status on CpG islands and pericentromeric satellite regions during human hepatocarcinogenesis

Illegitimate DNA integration in mammalian cells

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