TET2 functions as a resistance factor against DNA methylation acquisition during Epstein-Barr virus infection

Namba-Fukuyo, Hiroe; Funata, Sayaka; Matsusaka, Keisuke; Fukuyo, Masaki; Rahmutulla, Bahityar; Mano, Yasunobu; Fukayama, Masashi; Aburatani, Hiroyuki; Kaneda, Atsushi

doi:10.18632/oncotarget.13130

Cited by 51 publications

(48 citation statements)

References 36 publications

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“…However, further studies are needed to elucidate whether the expressional upregulation results in an increased protein level and causes the observed demethylation. In contrast to the HHV-6B effect, TET2 expression is repressed by EBV infection and, as expected, loss of TET2 increases EBV-induced host cell DNA methylation (31). However, TET2-induced hydroxymethylation of EBV promoters can also affect EBV reactivation from latency (32) and can affect the EBV latency type (33).…”

Section: Discussionsupporting

confidence: 58%

Human Herpesvirus 6B Induces Hypomethylation on Chromosome 17p13.3, Correlating with Increased Gene Expression and Virus Integration

Engdahl

Dunn

Niehusmann

et al. 2017

J Virol

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Human herpesvirus 6B (HHV-6B) is a neurotropic betaherpesvirus that achieves latency by integrating its genome into host cell chromosomes. Several viruses can induce epigenetic modifications in their host cells, but no study has investigated the epigenetic modifications induced by HHV-6B. This study analyzed methylation with an Illumina 450K array, comparing HHV-6B-infected and uninfected Molt-3 T cells 3 days postinfection. Bisulfite pyrosequencing was used to validate the Illumina results and to investigate methylation over time Expression of genes was investigated using quantitative PCR (qPCR), and virus integration was investigated with PCR. A total of 406 CpG sites showed a significant HHV-6B-induced change in methylation Remarkably, 86% (351/406) of these CpGs were located <1 Mb from chromosomal ends and were all hypomethylated in virus-infected cells. This was most evident at chromosome 17p13.3, where HHV-6B had induced CpG hypomethylation after 2 days of infection, possibly through TET2, which was found to be upregulated by the virus. In addition, virus-induced cytosine hydroxymethylation was observed. Genes located in the hypomethylated region at 17p13.3 showed significantly upregulated expression in HHV-6B-infected cells. A temporal experiment revealed HHV-6B integration in Molt-3 cell DNA 3 days after infection. The telomere at 17p has repeatedly been described as an integration site for HHV-6B, and we show for the first time that HHV-6B induces hypomethylation in this region during acute infection, which may play a role in the integration process, possibly by making the DNA more accessible. The ability to establish latency in the host is a hallmark of herpesviruses, but the mechanisms differ. Human herpesvirus 6B (HHV-6B) is known to establish latency through integration of its genome into the telomeric regions of host cells, with the ability to reactivate. Our study is the first to show that HHV-6B specifically induces hypomethylated regions close to the telomeres and that integrating viruses may use the host methylation machinery to facilitate their integration process. The results from this study contribute to knowledge of HHV-6B biology and virus-host interaction. This in turn will lead to further progress in our understanding of the underlying mechanisms by which HHV-6B contributes to pathological processes and may have important implications in both disease prevention and treatment.

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Section: Discussionsupporting

confidence: 58%

Human Herpesvirus 6B Induces Hypomethylation on Chromosome 17p13.3, Correlating with Increased Gene Expression and Virus Integration

Engdahl

Dunn

Niehusmann

et al. 2017

J Virol

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“…LMP2A induces the STAT3 phosphorylation followed by DNMT1 transcriptionally activation and PTEN promoter methylation, indicating LMP2A plays an essential role in the development and maintenance of EBV-associated cancer [143]. Besides, a resistance factor against DNA methylation namely TET2 was suppressed to contribute to DNA methylation acquisition during EBV infection [144]. Variety of tumor-suppressor genes have been identified to be methylated during EBV infection, such as p16, p14, APC, SSTR1, FHIT, CRBP1, WWOX, DLC-1, AQP3, REC8, TP73, BLU, FSD1, BCL7A, MARK1, SCRN1, and NKX3.1 [129,[145][146][147][148][149][150][151].…”

Section: Genetic and Epigenetic Abnormalities Of Host Cells In Ebvagcmentioning

confidence: 99%

Gastric cancer: genome damaged by bugs

et al. 2020

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Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. The role of the microorganisms in gastric tumorigenesis attracts much attention in recent years. These microorganisms include bacteria, virus, and fungi. Among them, Helicobacter pylori (H. pylori) infection is by far the most important risk factor for GC development, with special reference to the early-onset cases. H. pylori targets multiple cellular components by utilizing various virulence factors to modulate the host proliferation, apoptosis, migration, and inflammatory response. Epstein-Barr virus (EBV) serves as another major risk factor in gastric carcinogenesis. The virus protein, EBER noncoding RNA, and EBV miRNAs contribute to the tumorigenesis by modulating host genome methylation and gene expression. In this review, we summarized the related reports about the colonized microorganism in the stomach and discussed their specific roles in gastric tumorigenesis. Meanwhile, we highlighted the therapeutic significance of eradicating the microorganisms in GC treatment.

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“…We recently showed that TET2 5hmC modifies the EBV genome to promote lytic gene expression in epithelial cells and that NPC tumors lose TET2 expression, which may enhance oncogenesis (47). Furthermore, TET2 was recently found to be a resistance factor of EBV-induced DNA methylation in gastric carcinoma cells, demonstrating that TET2 may have an important role in protection against EBV ϩ tumor development (55). Thus, regulation of TET2 activity may play critical roles in the development of both epithelial and B cell malignancies associated with EBV.…”

Section: Tet2 Promotes Ebv Type III Latency Gene Expressionmentioning

confidence: 99%

Restricted TET2 Expression in Germinal Center Type B Cells Promotes Stringent Epstein-Barr Virus Latency

Wille

et al. 2017

J Virol

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Epstein-Barr virus (EBV) latently infects normal B cells and contributes to the development of certain human lymphomas. Newly infected B cells support a highly transforming form (type III) of viral latency; however, long-term EBV infection in immunocompetent hosts is limited to B cells with a more restricted form of latency (type I) in which most viral gene expression is silenced by promoter DNA methylation. How EBV converts latency type is unclear, although it is known that type I latency is associated with a germinal center (GC) B cell phenotype, and type III latency with an activated B cell (ABC) phenotype. In this study, we have examined whether expression of TET2, a cellular enzyme that initiates DNA demethylation by converting 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), regulates EBV latency type in B cells. We found that TET2 expression is inhibited in normal GC cells and GC type lymphomas. In contrast, TET2 is expressed in normal naive B cells and ABC type lymphomas. We also demonstrate that GC type cell lines have increased 5mC levels and reduced 5hmC levels in comparison to those of ABC type lines. Finally, we show that TET2 promotes the ability of the EBV transcription factor EBNA2 to convert EBV-infected cells from type I to type III latency. These findings demonstrate that TET2 expression is repressed in GC cells independent of EBV infection and suggest that TET2 promotes type III EBV latency in B cells with an ABC or naive phenotype by enhancing EBNA2 activation of methylated EBV promoters.IMPORTANCE EBV establishes several different types of viral latency in B cells. However, cellular factors that determine whether EBV enters the highly transforming type III latency, versus the more restricted type I latency, have not been well characterized. Here we show that TET2, a cellular enzyme that initiates DNA demethylation by converting 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), regulates EBV latency type in B cells by enhancing the ability of the viral transcription factor EBNA2 to activate methylated viral promoters that are expressed in type III (but not type I) latency. Furthermore, we demonstrate that (independent of EBV) TET2 is turned off in normal and malignant germinal center (GC) B cells but expressed in other B cell types. Thus, restricted TET2 expression in GC cells may promote type I EBV latency. KEYWORDS 5hmC, EBNA2, EBV, Epstein-Barr virus, TET2, germinal center B cell, latency E pstein-Barr virus (EBV) is human gammaherpesvirus that infects over 90% of the world population. EBV is the causative agent of infectious mononucleosis and is also associated with several malignancies of B cell and epithelial cell origin, including Burkitt lymphoma (BL), Hodgkin's disease, posttransplant lymphoproliferative disorder, diffuse large B cell lymphoma (DLBCL), nasopharyngeal carcinoma (NPC), and gastric carcinoma (1, 2). EBV establishes latent infection in normal B cells, in which the virus

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TET2 functions as a resistance factor against DNA methylation acquisition during Epstein-Barr virus infection

Cited by 51 publications

References 36 publications

Human Herpesvirus 6B Induces Hypomethylation on Chromosome 17p13.3, Correlating with Increased Gene Expression and Virus Integration

Human Herpesvirus 6B Induces Hypomethylation on Chromosome 17p13.3, Correlating with Increased Gene Expression and Virus Integration

Gastric cancer: genome damaged by bugs

Restricted TET2 Expression in Germinal Center Type B Cells Promotes Stringent Epstein-Barr Virus Latency

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