Induction of Hepatitis B Virus Core Gene in Human Cells by Cytosine Demethylation in the Promoter

Korba, Brent E.; Wilson, Vincent L.; Yoakum, George H.

doi:10.1126/science.2581318

Cited by 26 publications

(14 citation statements)

References 18 publications

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“…Similarly, 5-azacytidine-induced transcriptional activation of the Epstein-Barr virus latency C promoter was found to be the result of demethylation at a single CpG site (61). In the hepatitis B virus core gene, methylation of a single Hpa II site at -280 bp regulated the expression of the core gene (62). In the p53 promoter, a single-site methylation at -450 bp reduced gene expression in reporter gene constructs (42).…”

Section: Discussionmentioning

confidence: 99%

Association between the abnormal expression of matrix‐degrading enzymes by human osteoarthritic chondrocytes and demethylation of specific CpG sites in the promoter regions

Roach

Yamada

Cheung

et al. 2005

Arthritis & Rheumatism

306

273

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Objective. To investigate whether the abnormal expression of matrix metalloproteinases (MMPs) 3, 9, and 13 and ADAMTS-4 by human osteoarthritic (OA) chondrocytes is associated with epigenetic "unsilencing."Methods. Cartilage was obtained from the femoral heads of 16 patients with OA and 10 control patients with femoral neck fracture. Chondrocytes with abnormal enzyme expression were immunolocalized. DNA was extracted, and the methylation status of the promoter regions of MMPs 3, 9, and 13 and ADAMTS-4 was analyzed with methylation-sensitive restriction enzymes, followed by polymerase chain reaction amplification.Results. Very few chondrocytes from control cartilage expressed the degrading enzymes, whereas all clonal chondrocytes from late-stage OA cartilage were immunopositive. The overall percentage of nonmethylated sites was increased in OA patients (48.6%) compared with controls (20.1%): 20% versus 4% for MMP-13, 81% versus 47% for MMP-9, 57% versus 30% for MMP-3, and 48% versus 0% for ADAMTS-4. Not all CpG sites were equally susceptible to loss of methylation. Some sites were uniformly methylated, whereas in others, methylation was generally absent. For each enzyme, there was 1 specific CpG site where the demethylation in OA patients was significantly higher than that in controls: at -110 for MMP-13, -36 for MMP-9, -635 for MMP-3, and -753 for ADAMTS-4.Conclusion. This study provides the first evidence that altered synthesis of cartilage-degrading enzymes by late-stage OA chondrocytes may have resulted from epigenetic changes in the methylation status of CpG sites in the promoter regions of these enzymes. These changes, which are clonally transmitted to daughter cells, may contribute to the development of OA.Osteoarthritis (OA) is characterized by the progressive failure of the extracellular cartilage matrix, which leads to the destruction of articular cartilage (1,2). Primary OA is a late-onset complex disease with genetic, mechanical, and environmental components. Concordance of the disease in monozygotic twins is 40-60%, and the overall contribution of genetic factors is estimated to be ϳ50% (3). Given that more than 60% of unrelated adults over the age of 60 years are affected, other factors must also play a role in the development of this disease. Age, obesity, abnormal joint loading, and sports injuries are all risk factors, but OA is more than just the result of "wear and tear" (4,5). Articular chondrocytes are increasingly being suspected of playing major roles in the initiation and progression of the disease (1). This warrants closer examination of the cellular changes that occur in OA.The main extracellular matrix components of articular cartilage are collagens (principally, types II, IX, and XI) and proteoglycans (mainly, aggrecan). The major enzymes that mediate the destructive processes are aggrecanases 1 and 2 (ADAMTS-4 and ADAMTS-5) and matrix metalloproteinases (MMPs) 2 (gelatinase A),

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Section: Discussionmentioning

confidence: 99%

Association between the abnormal expression of matrix‐degrading enzymes by human osteoarthritic chondrocytes and demethylation of specific CpG sites in the promoter regions

Roach

Yamada

Cheung

et al. 2005

Arthritis & Rheumatism

306

273

View full text Add to dashboard Cite

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“…Similarly, treatment with 5-AZC induced Epstein-Barr virus early antigens in latently infected human lymphoid cells (Ben-Sasson et al, 1981). Furthermore, an increase in hepatitis B virus core transcripts (Korba et al, 1985) as well as expression of retrovirus type C and type A sequences (Hsiao et al, 1986;Lasneret et al, 1983) and genomes (Jaenisch et al, 1985) have been demonstrated after 5-AZC treatment. We therefore hypothesized that methylation of the HSV genome might be involved in the induction 0000-8084 © 1988 SGM Short communication or maintenance of the latent state by down-regulating viral gene expression and that druginduced hypomethylation might, therefore, enhance reactivation of latent HSV-2.…”

mentioning

confidence: 87%

Enhanced in vitro Reactivation of Herpes Simplex Virus Type 2 from Latently Infected Guinea-pig Neural Tissues by 5-Azacytidine

Stephanopoulos

Kappes

Bernstein

1988

Journal of General Virology

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SUMMARY5-Azacytidine (5-AZC) reduces cytosine methylation in DNA and has been reported to activate quiescent virus genes. Treatment of explant cultures of latently herpes simplex virus type 2 (HSV-2)-infected guinea-pig dorsal root ganglia and spinal cords in vitro with 5-AZC significantly enhanced the rate of HSV recovery. Both the number of isolates from ganglia (P < 0.001) and the rate of recovery (P < 0.001) were significantly increased with the addition of 50 ~tM-5-AZC to explant cultures. Increased virus recovery appeared to be due to the induction of reactivation of latent virus, rather than an increase in replication, since 5-AZC inhibited HSV replication. These data support a role for methylation in HSV latency and reactivation.

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“…Not only endogenous genes are subjected to this kind of epigenetic modifications but also certain human DNA tumour viruses such as EpsteimBarr virus (Masucci et al, 1989) and the hepatitis B virus (Korba et al, 1985) which take advantage of this host cell control mechanism as a regulatory pathway to modulate virusspecific gene expression at the transcriptional level. In the present investigation, evidence is provided that the activity of the U R R of pathogenic HPV-18 can also be altered by DNA methylation.…”

Section: Discussionmentioning

confidence: 99%

The Effect of DNA Methylation on Gene Regulation of Human Papillomaviruses

Rösl

Arab

Klevenz

et al. 1993

Journal of General Virology

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Integration of human papillomaviruses (HPVs) into the host genome is considered to be an early and important event in HPV-linked cervical carcinogenesis. Consequently, the viral DNA potentially becomes a target for cellular control mechanisms normally acting on the corresponding integration site. Besides resulting position effects, host-specific DNA methylation may play a functional role in HPV gene regulation. To elucidate the influence of such a kind of epigenetic modification on viral transcription, in vitro methylation studies on HPV-18 upstream regulatory region (URR)-controlled reporter plasmids were carded out. Selective methylation of the viral URR results in a down-regulation of the transcriptional activity, which can be attributed to nonrandom distribution of methyl-acceptor sites clustered within the constitutive enhancer region. In vivo competition experiments show that suppression is not directly mediated by steric hindrance of methyl residues with transcription factors, but rather is due to the association with methyl-CpG DNA-binding proteins. Using a restriction enzyme accessibility assay on both the DNA and chromatin levels, it could be demonstrated that, in vivo, extensively methylated viral DNA is nucleosomally organized, characteristic of transcriptionally inactive chromatin. These data suggest that DNA methylation is an important regulatory pathway in the modulation of HPV expression and as a consequence the proliferation rate of virus-infected cells.

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Induction of Hepatitis B Virus Core Gene in Human Cells by Cytosine Demethylation in the Promoter

Cited by 26 publications

References 18 publications

Association between the abnormal expression of matrix‐degrading enzymes by human osteoarthritic chondrocytes and demethylation of specific CpG sites in the promoter regions

Association between the abnormal expression of matrix‐degrading enzymes by human osteoarthritic chondrocytes and demethylation of specific CpG sites in the promoter regions

Enhanced in vitro Reactivation of Herpes Simplex Virus Type 2 from Latently Infected Guinea-pig Neural Tissues by 5-Azacytidine

The Effect of DNA Methylation on Gene Regulation of Human Papillomaviruses

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