Epigenetic dysregulation of the host cell genome in Epstein–Barr virus-associated neoplasia

Niller, Hans Helmut; Wolf, Hans; Minárovits, János

doi:10.1016/j.semcancer.2009.02.012

Cited by 109 publications

(86 citation statements)

References 122 publications

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“…We demonstrated that methylation accumulates in the MHV68 distal gene 50 promoter region over time. Studies with EBV and KSHV have also described methylated latent genomes in both normal and tumor cells (8,14,35,37,38). One model proposes that gammaherpesviruses infect naïve B lymphocytes and, thus, are exposed to the unique environment of the germinal center following B-cell activation.…”

Section: Discussionmentioning

confidence: 99%

The De Novo Methyltransferases DNMT3a and DNMT3b Target the Murine Gammaherpesvirus Immediate-Early Gene 50 Promoter during Establishment of Latency

Gray

Forrest

Speck

2010

J Virol

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The role of epigenetic modifications in the regulation of gammaherpesvirus latency has been a subject of active study for more than 20 years. DNA methylation, associated with transcriptional silencing in mammalian genomes, has been shown to be an important mechanism in the transcriptional control of several key gammaherpesvirus genes. In particular, DNA methylation of the functionally conserved immediate-early replication and transcription activator (RTA) has been shown to regulate Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus Rta expression. Here we demonstrate that the murine gammaherpesvirus (MHV68) homolog, encoded by gene 50, is also subject to direct repression by DNA methylation, both in vitro and in vivo. We observed that the treatment of latently MHV68-infected B-cell lines with a methyltransferase inhibitor induced virus reactivation. In addition, we show that the methylation of the recently characterized distal gene 50 promoter represses activity in a murine macrophage cell line. To evaluate the role of de novo methyltransferases (DNMTs) in the establishment of these methylation marks, we infected mice in which conditional DNMT3a and DNMT3b alleles were selectively deleted in B lymphocytes. DNMT3a/DNMT3b-deficient B cells were phenotypically normal, displaying no obvious compromise in cell surface marker expression or antibody production either in naïve mice or in the context of nonviral and viral immunogens. However, mice lacking functional DNMT3a and DNMT3b in B cells exhibited hallmarks of deregulated MHV68 lytic replication, including increased splenomegaly and the presence of infectious virus in the spleen at day 18 following infection. In addition, total gene 50 transcript levels were elevated in the spleens of these mice at day 18, which correlated with the hypomethylation of the distal gene 50 promoter. However, by day 42 postinfection, aberrant virus replication was resolved, and we observed wild-type frequencies of viral genomepositive splenocytes in mice lacking functional DNMT3a and DNMT3b in B lymphocytes. The latter correlated with increased CpG methylation in the distal gene 50 promoter, which was restored to levels similar to those of littermate controls harboring functional DNMT3a and DNMT3b alleles in B lymphocytes, suggesting the existence of an alternative mechanism for the de novo methylation of the MHV68 genome. Importantly, this DNMT3a/DNMT3b-independent methylation appeared to be targeted specifically to the gene 50 promoter, as we observed that the promoters for MHV68 gene 72 (v-cyclin) and M11 (v-bcl2) remained hypomethylated at day 42 postinfection. Taken together, these data provide the first evidence of the importance of DNA methylation in regulating gammaherpesvirus RTA/gene 50 transcription during virus infection in vivo and provide insight into the hierarchy of host machinery required to establish this modification.Herpesviruses are large, double-stranded DNA viruses characterized by distinct lytic and latent stages. Upon initial infection, the virus un...

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Section: Discussionmentioning

confidence: 99%

The De Novo Methyltransferases DNMT3a and DNMT3b Target the Murine Gammaherpesvirus Immediate-Early Gene 50 Promoter during Establishment of Latency

Gray

Forrest

Speck

2010

J Virol

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“…To evade immune destruction and promote lifelong persistence of viral infection, EBV gene expression is normally restricted to nonimmunogenic factors such as EBER transcripts and microRNAs (type 0 latency) that can inhibit apoptosis (39,46,88,132). Some mucosal B lymphocytes additionally express EBNA1 (type 1 latency), which maintains the EBV genome and ensures its propagation to dividing cells (209), and LMP1 and LMP2 (type II latency), which mimic B cell receptor stimulation with JAK/STAT signaling to promote cell proliferation, inhibit apoptosis, and generate long-lived memory B cells (22,200).…”

Section: Viral Gene Expression Patternsmentioning

confidence: 99%

Using Epstein-Barr Viral Load Assays To Diagnose, Monitor, and Prevent Posttransplant Lymphoproliferative Disorder

2010

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SUMMARYEpstein-Barr virus (EBV) DNA measurement is being incorporated into routine medical practice to help diagnose, monitor, and predict posttransplant lymphoproliferative disorder (PTLD) in immunocompromised graft recipients. PTLD is an aggressive neoplasm that almost always harbors EBV DNA within the neoplastic lymphocytes, and it is often fatal if not recognized and treated promptly. Validated protocols, commercial reagents, and automated instruments facilitate implementation of EBV load assays by real-time PCR. When applied to either whole blood or plasma, EBV DNA levels reflect clinical status with respect to EBV-related neoplasia. While many healthy transplant recipients have low viral loads, high EBV loads are strongly associated with current or impending PTLD. Complementary laboratory assays as well as histopathologic examination of lesional tissue help in interpreting modest elevations in viral load. Circulating EBV levels in serial samples reflect changes in tumor burden and represent an effective, noninvasive tool for monitoring the efficacy of therapy. In high-risk patients, serial testing permits early clinical intervention to prevent progression toward frank PTLD. Restoring T cell immunity against EBV is a major strategy for overcoming PTLD, and novel EBV-directed therapies are being explored to thwart virus-driven neoplasia.

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“…The epigenetic effect of EBV disrupts host gene regulation in a way that is preferential for EBV survival, and is shown to be associated with several EBV-related neoplasms. 88,89 For example, an EBV-encoded gene, latent membrane protein 1, induces the expression of DNA methyltransferases, 90 which induce hypermethylation of tumor suppressor genes. 89 In addition, several viral miRNAs encoded in the EBV genome are known to regulate the expression of host genes.…”

Section: Epigenetic Effects Of Environmental Risk Factors For Msmentioning

confidence: 99%

Epigenetics in multiple sclerosis

Miyazaki

Niino

2015

Clinical & Exp Neuroim

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The development of multiple sclerosis (MS) is based on complex interactions between genetic and environmental factors. Epigenetic regulation is a biological phenomenon defined as the modification of gene expression without alteration of the DNA sequence, and is currently thought to underlie the interactions between the genetic and environmental risks of MS. The molecular mechanisms of epigenetics include DNA methylation, histone modification, and microRNAs. Observational data obtained from epidemiological studies of MS, such as the parent-of-origin effect and the longitudinal increase in female patients, suggest that epigenetic mechanisms are involved in MS development, although the molecular basis remains unclear. Interestingly, environmental factors related to the development of MS, such as Epstein-Barr virus, smoking, and vitamin D, have been shown to regulate gene expression through epigenetic mechanisms in some experimental settings. One study showed no reproducible differences among DNA methylation profiles in peripheral blood CD4 + T cells between three monozygotic twin pairs discordant for MS. However, several studies have shown that dysregulated DNA methylation of genes is related to abnormal immune reactions and post-translational modifications of myelin proteins in MS brain samples. In addition, abnormal microRNA profiles have been reported in brain tissues and peripheral blood immune cells obtained from MS patients. In this article, we will review the studies on the epigenetics of MS and discuss the perspectives for future research.

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Epigenetic dysregulation of the host cell genome in Epstein–Barr virus-associated neoplasia

Cited by 109 publications

References 122 publications

The De Novo Methyltransferases DNMT3a and DNMT3b Target the Murine Gammaherpesvirus Immediate-Early Gene 50 Promoter during Establishment of Latency

The De Novo Methyltransferases DNMT3a and DNMT3b Target the Murine Gammaherpesvirus Immediate-Early Gene 50 Promoter during Establishment of Latency

Using Epstein-Barr Viral Load Assays To Diagnose, Monitor, and Prevent Posttransplant Lymphoproliferative Disorder

Epigenetics in multiple sclerosis

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