Host cell phenotype-dependent methylation patterns of Epstein--Barr virus DNA

Minárovits, János; Minarovits-Kormuta, S.; Ehlin‐Henriksson, Barbro; Falk, Kerstin I.; Klein, George; Ernberg, Ingemar

doi:10.1099/0022-1317-72-7-1591

Cited by 52 publications

(46 citation statements)

References 33 publications

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“…These findings demonstrate that methylation does not spread regardless of transcriptional activity or patch size of methylation. This suggests that inactive chromatin is not likely to be the cause of de novo methylation observed in integrated (26) or episomal (6,21) EBV DNA or at sites in the genome. Although it is possible that the integrated or genomic sequences and episomal DNA are sequestered in different nuclear compartments, it is highly unlikely that episomal EBV DNA is in a nuclear compartment different from this oriPbased minichromosome.…”

Section: Discussionmentioning

confidence: 90%

Stability of Patch Methylation and Its Impact in Regions of Transcriptional Initiation and Elongation

Hsieh

1997

Molecular and Cellular Biology

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CpG DNA methylation has previously been correlated with the suppression of transcription. The mechanism of this suppression is not understood, and many aspects of the temporal and positional relationships between the region of methylation and transcription have not yet been defined. Here, 12-kb stable replicating episomes that can be maintained in human somatic cells for weeks to months were used. Such a system allows more direct manipulation and is free from the positional effects attendant with the analysis of endogenous loci or integrated transgenes. By using these circular minichromosomes, patches of CpG methylation were created to include or exclude the regions of transcriptional initiation and elongation. I found that a 0.5-kb patch of methylation that covered the promoter suppressed expression only 2-fold and that a 1.9-kb patch of methylation that covered the coding portion of the gene (but not the promoter) suppressed expression about 10-fold. In contrast, methylation of the entire minichromosome except for the promoter or the coding portion suppressed transcription about 50-to 200-fold. I infer the following. Methylation of the 0.5-kb promoter fragment does not significantly affect transcription at the level of transcription factor binding or local chromatin structure. The dominant effect on transcription occurs when the length of methylated DNA is long, with little disproportionate effect of methylation of specific regions, such as that of initiation or elongation. I also found that the boundaries between these methylated and unmethylated regions remained stable for the many weeks that I monitored them.CpG methylation has previously been associated with reduced transcription (see references 2 and 23 for reviews), decreased DNase I sensitivity (16), and decreased site-specific recombination (10). The repressive aspects of chromatin structure specified by CpG methylation have not yet been identified.CpG methylation is tightly regulated during replication and differentiation of somatic cells. A maintenance methyltransferase functions during DNA replication to preserve the methylated pattern of preexisting methylated regions (18) (for a review, see reference 3). In general, genes lose CpG methylation within the promoter and in the transcribed region of the gene when they become activated, whereas genes acquire CpG methylation when they are no longer transcribed (for reviews, see references 4 and 24). However, it is not clear how regions of DNA become demethylated, how they acquire methylation in somatic cells, and over what time intervals these changes occur.Many basic questions regarding CpG methylation remain unanswered. Does methylation specifically in the regions of initiation or elongation inhibit the transcription process? Do methylation of the promoter and methylation of the coding region of the gene have different effects on transcription? What length and density of CpG methylation are sufficient to affect the transcriptional activity of an adjacent unmethylated region? Is the boundary between a m...

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Section: Discussionmentioning

confidence: 90%

Stability of Patch Methylation and Its Impact in Regions of Transcriptional Initiation and Elongation

Hsieh

1997

Molecular and Cellular Biology

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“…The quiescent genomes of retroviruses, adenoviruses and herpesviruses in their respective latently infected cells have been shown to be heavily methylated at 5' CpG 3' residues (Desrosiers et al, 1979;Groudine et al, 1981;Hoffman et al, 1982;Kanamori et al, 1987;Minarovits et al, 1991). Moreover, inhibition of 5' CpGY methylation with 5-azacytidine has been associated with the reactivation of such latent genomes (Ben-Sasson & Klein, 1981;Groudine et al, 1981;Hoffman et al, 1982;Niwa & Sugahara, 1981).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, we have shown that the MDV genome in these ALV tumour cell lines is likely to be modified by methylation of 5' CpG 3' dinucleotides, a characteristic of inactive herpesvirus genomes (Desrosiers et al, 1979;Kanamori et al, 1987;Minarovits et al, 1991;Youssoufian et al, 1982).…”

Section: D V Dna Is Highly Methylated In a L V Tumourderived Cell Lmentioning

confidence: 99%

Latency and reactivation of Marek's disease virus in B lymphocytes transformed by avian leukosis virus

Fynan

Ewert

Block

1993

Journal of General Virology

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The physical and biological state of the Marek's disease virus (MDV) genome in avian leukosis virus (ALV)-transformed cells is characterized using cell lines established from ALV tumours co-infected with the SB-1 strain of MDV. The MDV genome within the ALVtransformed cells was found to be methylated at 5' CpG 3' dinucleotides. Less than 2% of the tumour cells expressed MDV antigen and only one virus plaque that was characteristic of an MDV infection was noted when tumour cells were cocultured with fibroblasts permissive for a productive MDV infection. However, when methylation of the MDV genome was prevented by culturing the tumour cell lines in the presence of 5-azacytidine, both MDV antigen expression and viral replication increased. Based on these results, it appears that MDV resides within the ALV-transformed cells in a latent state and that MDV latency might be influenced, to some extent, by methylation of the MDV genome.

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“…Although in most Burkitt's lymphoma the virus displays a latency I program, unusual forms of latency have also been identified (1)(2)(3). Moreover, upon cultivation in vitro, BL cells tend to change their phenotype toward an LCL-like phenotype by broadening the pattern of EBV latent gene expression (4).…”

Section: Introductionmentioning

confidence: 99%

Resveratrol Inhibits Proliferation and Survival of Epstein Barr Virus–Infected Burkitt's Lymphoma Cells Depending on Viral Latency Program

Leo

Arena

Stecca

et al. 2011

Molecular Cancer Research

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Resveratrol (3,4 0 ,5-trihydroxy-trans-stilbene), a polyphenolic natural product, shows chemopreventive properties against several cancers, heart diseases, inflammation, and viral infections. Epstein Barr virus (EBV), a g-herpesvirus, contributes to the development of several human cancers including Burkitt's lymphoma (BL). In this study, we asked whether treatment with resveratrol would affect the viability of EBV-positive BL cells displaying different forms of latency. We report here that resveratrol, regardless of EBV status, induces caspasedependent apoptosis by arresting cell-cycle progression in G 1 phase. However, resveratrol strongly induced apoptosis in EBV(À) and latency I EBV(þ) cells, whereas latency II and latency III EBV(þ) BL cells showed a survival advantage that increased with the extent of the pattern of viral gene expression. Resveratrol-induced cellcycle arrest and apoptosis occurred in association with induction of p38 MAPK phosphorylation and suppression of ERK1/2 signaling pathway. Moreover, NF-kB DNA-binding activity was inhibited in all BL lines except EBV (þ) latency III cells.LMP1 oncogene, which is expressed in latency III phenotype, is involved with the higher resistance to the antiproliferative effect of resveratrol because siRNA-mediated inhibition of LMP1 greatly increased the sensitivity of latency III BL cells as well as that of lymphoblastoid cell lines to the polyphenol. We propose that a combined resveratrol/siRNA strategy may be a novel approach for the treatment of EBV-associated B-cell malignancies in which the viral pattern of gene expression has been defined. Mol Cancer Res; 9(10); 1346-55. Ó2011 AACR.

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Host cell phenotype-dependent methylation patterns of Epstein--Barr virus DNA

Cited by 52 publications

References 33 publications

Stability of Patch Methylation and Its Impact in Regions of Transcriptional Initiation and Elongation

Stability of Patch Methylation and Its Impact in Regions of Transcriptional Initiation and Elongation

Latency and reactivation of Marek's disease virus in B lymphocytes transformed by avian leukosis virus

Resveratrol Inhibits Proliferation and Survival of Epstein Barr Virus–Infected Burkitt's Lymphoma Cells Depending on Viral Latency Program

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