Epstein–Barr virus and host cell methylation: regulation of latency, replication and virus reactivation

Woellmer, Anne; Hammerschmidt, Wolfgang

doi:10.1016/j.coviro.2013.03.005

Cited by 69 publications

(60 citation statements)

References 22 publications

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“…Once established, EBV genome methylation is maintained during latent viral genome replication (licensed and mediated by host cell replication machinery) via the enzymatic activity of DNA methyltransferases (1,2). However, the virally encoded replication machinery mediating the lytic form of viral DNA replication does not preserve viral genome methylation (9,11), and therefore, packaged EBV genomes are always unmethylated.…”

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confidence: 99%

“…CpG methylation of the EBV genome is detectable within 2 wk postinfection in B cells (10) and plays a critical role in promoting the most stringent (and least immunogenic) form of viral latency (reviewed in refs. 11,12). In addition, methylation of the viral genome is required for the ability of the EBV BZLF1 (Z) immediate-early protein to induce the latent to lytic switch, because Z preferentially binds to and activates the methylated forms of lytic EBV promoters (reviewed in refs.…”

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confidence: 99%

“…11,13). Z (also known as EB1, ZEBRA, and Zta) is a bZip protein homologous to AP-1 and binds to AP-1-like sites (Z-responsive elements, ZREs) that often contain CpG motifs (11,(13)(14)(15). Once established, EBV genome methylation is maintained during latent viral genome replication (licensed and mediated by host cell replication machinery) via the enzymatic activity of DNA methyltransferases (1,2).…”

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confidence: 99%

“…In addition, methylation of the viral genome is required for the ability of the EBV BZLF1 (Z) immediate-early protein to induce the latent to lytic switch, because Z preferentially binds to and activates the methylated forms of lytic EBV promoters (reviewed in refs. 11,13). Z (also known as EB1, ZEBRA, and Zta) is a bZip protein homologous to AP-1 and binds to AP-1-like sites (Z-responsive elements, ZREs) that often contain CpG motifs (11,(13)(14)(15).…”

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5-hydroxymethylation of the EBV genome regulates the latent to lytic switch

Wille

Nawandar

Henning

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Latent Epstein-Barr virus (EBV) infection and cellular hypermethylation are hallmarks of undifferentiated nasopharyngeal carcinoma (NPC). However, EBV infection of normal oral epithelial cells is confined to differentiated cells and is lytic. Here we demonstrate that the EBV genome can become 5-hydroxymethylated and that this DNA modification affects EBV lytic reactivation. We show that global 5-hydroxymethylcytosine (5hmC)-modified DNA accumulates during normal epithelial-cell differentiation, whereas EBV+ NPCs have little if any 5hmC-modified DNA. Furthermore, we find that increasing cellular ten-eleven translocation (TET) activity [which converts methylated cytosine (5mC) to 5hmC] decreases methylation, and increases 5hmC modification, of lytic EBV promoters in EBV-infected cell lines containing highly methylated viral genomes. Conversely, inhibition of endogenous TET activity increases lytic EBV promoter methylation in an EBV-infected telomerase-immortalized normal oral keratinocyte (NOKs) cell line where lytic viral promoters are largely unmethylated. We demonstrate that these cytosine modifications differentially affect the ability of the two EBV immediateearly proteins, BZLF1 (Z) and BRLF1 (R), to induce the lytic form of viral infection. Although methylation of lytic EBV promoters increases Z-mediated and inhibits R-mediated lytic reactivation, 5hmC modification of lytic EBV promoters has the opposite effect. We also identify a specific CpG-containing Z-binding site on the BRLF1 promoter that must be methylated for Z-mediated viral reactivation and show that TET-mediated 5hmC modification of this site in NOKs prevents Z-mediated viral reactivation. Decreased 5-hydroxymethylation of cellular and viral genes may contribute to NPC formation.EBV | 5hmC | lytic reactivation | NPC

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5-hydroxymethylation of the EBV genome regulates the latent to lytic switch

Wille

Nawandar

Henning

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…El VEB puede infectar células epiteliales y de la línea linfoide, con especial tropismo por células B (3,4,9,15). Una vez en el interior celular, el virus es regulado por mecanismos epigenéticos y ha evolucionado para aprovechar la maquinaria epigenética de la célula huésped, establecer una infección latente y posteriormente avanzar a la fase productiva del ciclo lítico (16). Durante este proceso, el virus inmortaliza a la célula, estimula la proliferación, induce la expresión de BCL-2 y favorece la evasión de la apoptosis y la respuesta inmune (4,15).…”

Section: Asociación Del Virus De Epstein-barr Con Cáncerunclassified

Virus de Epstein-Barr y su relación con el desarrollo del cáncer

Medina-Ortega

López-Valencia

Mosquera-Monje

et al. 2017

iatreia

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RESUMENEl virus de Epstein-Barr (VEB) es un agente infeccioso que tiene tropismo por células linfoides y ocasionalmente por células epiteliales. La Agencia Internacional para la Investigación sobre Cáncer (IARC, por su sigla en inglés) lo clasificó hace 20 años como carcinógeno de tipo I, porque durante la infección latente expresa diferentes proteínas o micro-ARN con capacidad oncogénica, por lo que las células infectadas tendrían el potencial de desarrollar cáncer. Esto se ha demostrado en algunos tipos de cáncer como linfomas, carcinoma nasofaríngeo y cán-cer gástrico, mientras que la asociación no es completamente clara en los cánceres de mama y pulmón. La presente revisión describe, profundiza y analiza la relación del VEB con dichos tipos de cáncer, así como los métodos diagnósticos empleados para su detección. Finalmente, se plantean preguntas cuyas respuestas podrían contribuir al conocimiento de los mecanismos moleculares involucrados en la relación VEB-cáncer. PALABRAS CLAVE

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Epstein‐Barr virus mRNA profiles and viral DNA methylation status in nasopharyngeal brushings from nasopharyngeal carcinoma patients reflect tumor origin

Ramayanti

Juwana

Verkuijlen

et al. 2016

Intl Journal of Cancer

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Undifferentiated nasopharyngeal carcinoma (NPC) is 100% associated with Epstein‐Barr virus (EBV) as oncogenic driver. NPC is often diagnosed late due to initial vague complaints and obscured location. Prior studies suggest that measurement of EBV DNA load and RNA transcripts in nasopharyngeal (NP) brushings is useful for minimally invasive NPC diagnosis. However, whether these EBV markers relate to local virus replication or reflect tumor origin remains to be demonstrated. To resolve this, we analysed EBV‐DNA characteristics and quantified latent and lytic viral RNA transcripts in NP brushings and matching frozen NP‐biopsy specimens from patients suspected of having NPC.We observed non‐fragmented and Cp‐promotor methylated EBV‐DNA in both NP brushings and biopsies suggestive of tumor origin. Using quantitative RT‐PCR we determined expression levels of 7 critical latent (EBER1, Qp‐EBNA1, EBNA2, BART, LMP1, LMP2, BARF1) and 5 lytic (Zta, Rta, TK, PK and VCA‐p18) RNA transcripts. Although latent and early lytic RNA transcripts were frequently detected in conjunction with high EBV viral load, in both brushings and biopsies the latent transcripts prevailed and reflected a typical NPC‐associated latency‐II transcription profile without EBNA2. Late lytic RNA transcripts were rare and detected at low levels mainly in NP brushings, suggestive of abortive viral reactivation rather than complete virus replication. EBV‐IgA serology (EBNA1, VCA, Zta) did not correlate to the level of viral reactivation in situ.Overall, viral RNA profiling, DNA fragmentation and methylation analysis in NP brushings and parallel biopsies indicate that NP brush sampling provides a true and robust indicator of NPC tumor presence.

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Epstein–Barr virus and host cell methylation: regulation of latency, replication and virus reactivation

Cited by 69 publications

References 22 publications

5-hydroxymethylation of the EBV genome regulates the latent to lytic switch

5-hydroxymethylation of the EBV genome regulates the latent to lytic switch

Virus de Epstein-Barr y su relación con el desarrollo del cáncer

Epstein‐Barr virus mRNA profiles and viral DNA methylation status in nasopharyngeal brushings from nasopharyngeal carcinoma patients reflect tumor origin

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