Epigenetic regulation of latent Epstein–Barr virus promoters

Takács, Mária; Bánáti, Ferenc; Koroknai, Anita; Segesdi, Judit; Salamon, Dániel; Wolf, Hans; Niller, Hans Helmut; Minárovits, János

doi:10.1016/j.bbagrm.2009.10.005

Cited by 73 publications

(68 citation statements)

References 78 publications

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“…The latent infection is associated with several lymphoid and epithelial cell malignancies, especially the endemic forms of Burkitt's lymphoma and nasopharyngeal carcinoma (3,4). During latent infection, EBV persists as multicopy minichromosomes (referred to as episomes) that express a highly restricted set of viral genes (5,6). Latent cycle gene expression can vary depending on cell type, developmental stage, and environmental conditions (7).…”

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confidence: 99%

Epigenetic Deregulation of the LMP1/LMP2 Locus of Epstein-Barr Virus by Mutation of a Single CTCF-Cohesin Binding Site

Chen

Martin

Lü

et al. 2014

J Virol

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The chromatin regulatory factors CTCF and cohesin have been implicated in the coordinated control of multiple gene loci in Epstein-Barr virus (EBV) latency. We have found that CTCF and cohesin are highly enriched at the convergent and partially overlapping transcripts for the LMP1 and LMP2A genes, but it is not yet known how CTCF and cohesin may coordinately regulate these transcripts. We now show that genetic disruption of this CTCF binding site (EBV⌬CTCF166) leads to a deregulation of LMP1, LMP2A, and LMP2B transcription in EBV-immortalized B lymphocytes. EBV⌬CTCF166 virus-immortalized primary B lymphocytes showed a decrease in LMP1 and LMP2A mRNA and a corresponding increase in LMP2B mRNA. The reduction of LMP1 and LMP2A correlated with a loss of euchromatic histone modification H3K9ac and a corresponding increase in heterochromatic histone modification H3K9me3 at the LMP2A promoter region in EBV⌬CTCF166. Chromosome conformation capture (3C) revealed that DNA loop formation with the origin of plasmid replication (OriP) enhancer was eliminated in EBV⌬CTCF166. We also observed that the EBV episome copy number was elevated in EBV⌬CTCF166 and that this was not due to increased lytic cycle activity. These findings suggest that a single CTCF binding site controls LMP2A and LMP1 promoter selection, chromatin boundary function, DNA loop formation, and episome copy number control during EBV latency.

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mentioning

confidence: 99%

Epigenetic Deregulation of the LMP1/LMP2 Locus of Epstein-Barr Virus by Mutation of a Single CTCF-Cohesin Binding Site

Chen

Martin

Lü

et al. 2014

J Virol

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“…Unexpectedly, we observed that similarly to the carcinoma cell line of epithelial origin, there was a high level of LMNA transcription in LCLs and in the majority of group III BL lines characterized by an activated B cell phenotype. These cells express typically six nuclear antigens (EBNAs) and three latent membrane proteins (LMPs) encoded by the virus (EBV latency type III) [16]. In contrast, lamin A/C mRNA was present at a low level in EBV-negative B and BL lines and in EBV latency type I BL cell lines that expressed only EBNA1.…”

Section: Discussionmentioning

confidence: 95%

“…Because EBV can alter the epigenotype and gene expression pattern of its target cells, and lamins are epigenetic regulators themselves, we did a systematic analysis of lamin A/C expression in EBV-positive and EBV-negative B lymphoid cell lines and analyzed the epigenetic marks of LMNAp [1,16]. Unexpectedly, we observed that similarly to the carcinoma cell line of epithelial origin, there was a high level of LMNA transcription in LCLs and in the majority of group III BL lines characterized by an activated B cell phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…Epstein-Barr virus (EBV), a human gammaherpesvirus, is regularly associated with human lymphomas of B cell origin and immortalizes human B cells with a high efficiency in vitro [16]. The expression of latent EBV genomes is highly restricted in Burkitt lymphoma (BL) cells that phenotypically resemble resting B cells: only EBNA1, an EBV-encoded nuclear antigen, and a set of non-translated viral RNAs can be detected [17].…”

Section: Introductionmentioning

confidence: 99%

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Up-regulation of Lamin A/C Expression in Epstein-Barr Virus Immortalized B Cells and Burkitt Lymphoma Cell Lines of Activated B Cell Phenotype

Bánáti¹,

Koroknai

Szenthe³

et al. 2016

Preprint

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Lamin A, B and C, the nuclear intermediate-filament proteins, play a role in epigenetic regulation. While Lamin B is expressed in all nucleated cells studied, Lamin A/C are transcribed in most somatic cell types except mature B lymphocytes. Since Epstein-Barr virus (EBV), a human gammaherpesvirus, is associated with tumorigenic processes and is known to alter the epigenotype of its host cells, we studied the expression of the LMNA gene and its epigenetic marks in EBV-carrying human lymphoid cell lines. We observed a high lamin A/C mRNA and protein expression in EBV-immortalized lymphoblastoid cell lines (LCLs) and in group III Burkitt lymphoma (BL) lines where hypomethylated first exons were observed with activating histone marks. In most cell lines with low promoter activity a highly methylated first exon could be detected. Our data showed that methylation of the first exon of LMNA was associated with the downregulation of LMNA expression whereas euchromatic histone marks were enriched at active LMNA promoters in EBV-immortalized LCLs. These data suggest a role for viral latency products to activate LMNAp in EBV-infected latency type III B cells in vitro. Expression of lamin A/C may contribute to the establishment of activated B cell phenotype that needs further explorations.

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“…In order to neutralize host cell mRNAs, which are to be translated into defensive inflammatory proteins, the EBV genome generates numerous (may be over 25) microRNAs (EBERs) (474,475). The EBV genome BamHIA rightward fragment (BARF) and BamHI (Bacillus amyloliquefaciens endonuclease) fragment H rightward open reading frame (BHRF1) release the viral microRNAs most frequently in the case of type III latency in nasopharyngeal tissues.…”

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confidence: 99%

Molecular biology of oncogenic inflammatory processes. I. Non-oncogenic and oncogenic pathogens, intrinsic inflammatory reactions without pathogens, and microRNA/DNA interactions (Review)

Sinkovics

2011

Int J Oncol

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Abstract. In some inflammasomes tumor cells are generated. The internal environment of the inflammasome is conducive to the induction of malignant transformation. Epigenetic changes initiate this process. The subverted stromal connective tissue cells act to promote and sustain the process of malignant trans formation. In its early stages, the premalignant cells depend on paracrine circuitries for the reception of growth factors. The ligands are derived from the connective tissue, and the receptors are expressed on the recipient premalignant cells. The initial events are not a direct attack on the protooncogenes, and thus it may be entirely reversible. Epigenetic processes of hypermethylation of the genes at the promoters of tumor suppressor genes (to silence them), and deacetylation of the histones aimed at the promoters of protooncogenes (to activate them) are ongoing. A large number of short RNA sequences (interfering, micro, short hairpin, noncoding RNAs) silence tumor suppressor genes, by neutralizing their mRNAs. In a serial sequence oncogenes undergo amplifications, pointmutations, translocations and fusions. In its earliest stage, the process is reversible by demethylation of the silenced suppressor gene promoters (to reactivate them), or reacetylation of the histones of the oncogene promoters, thus deactivating them. The external administration of histone deacetylase inhibitors usually leads to the restoration of histone acetylation. In time, the uncorrected processes solidify into constitutive and irreversible gene mutations. Some of the pathogens inducing inflammations with consquential malignant transformation contain oncogenic gene sequences (papilloma viruses, EpsteinBarr virus, Kaposi's sarcomaassociated herpesvirus, hepatitis B and C viruses, Merkel cell polyoma virus, Helicobacter pylori, enterotoxigenic Bacteroides fragilis). These induced malignancies may be multifocal. Other pathogens are devoid of any known oncogenic genomic sequences (mycoplasma vavcarcinogenesis, chlamydia MALTlymphoma genesis). In these cases the host's inflammatory reactions induce the malignant transformation in serial sequences of gene alterations initiated by hypoxia and reactive oxygen and nitrogen species generation. Carcinogenic intrinsic inflammatory processes endogenously initiated without a pathogen are recognized. Chronic inflammatory processes signal the RNA/DNA complex. In response, the DNA may revert into its ancient primordial 'immortal' format, which the clinics recognize as 'oncogenesis'. The DNA remains the ultimate master of bioengineering in order to sustain life. A discussion on the most versatile and resistant primordial RNA/ DNA complex and the pre, proto, and unicellular world in which they coexisted is included. Contents1. Pathogens without oncogenic genomic sequences activating cellular oncogenes 2. The inflammasome 3. Tumor cell colonies generated in the inflammasomes 4. Pathogens with potentially oncogenic genomic sequences 5. Mechanisms of inflammatory carcinogenesis Pathogens without oncogenic...

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Epigenetic regulation of latent Epstein–Barr virus promoters

Cited by 73 publications

References 78 publications

Epigenetic Deregulation of the LMP1/LMP2 Locus of Epstein-Barr Virus by Mutation of a Single CTCF-Cohesin Binding Site

Epigenetic Deregulation of the LMP1/LMP2 Locus of Epstein-Barr Virus by Mutation of a Single CTCF-Cohesin Binding Site

Up-regulation of Lamin A/C Expression in Epstein-Barr Virus Immortalized B Cells and Burkitt Lymphoma Cell Lines of Activated B Cell Phenotype

Molecular biology of oncogenic inflammatory processes. I. Non-oncogenic and oncogenic pathogens, intrinsic inflammatory reactions without pathogens, and microRNA/DNA interactions (Review)

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