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

نویسندگان

  • Coral K Wille
  • Dhananjay M Nawandar
  • Amanda N Henning
  • Shidong Ma
  • Kayla M Oetting
  • Dennis Lee
  • Paul Lambert
  • Eric C Johannsen
  • Shannon C Kenney
چکیده

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 immediate-early 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.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

ZEB1 Regulates the Latent-Lytic Switch in Infection by Epstein-Barr Virus

The immediate-early (IE) BZLF1 gene of Epstein-Barr virus (EBV) regulates the switch between latent and lytic infection by EBV. We previously showed that the cellular transcription factor ZEB1 binds to a sequence element, ZV, located at nt -17 to -12 relative to the transcription initiation site of the BZLF1 promoter, Zp, repressing transcription from Zp in a transient transfection assay. Here,...

متن کامل

Regulation of Epstein-Barr virus lytic cycle activation in malignant and nonmalignant disease.

Like all other herpesviruses, the oncogenic human gammaherpesvirus, Epstein-Barr virus (EBV; human herpesvirus 4) manifests two distinct phases in its life cycle: latency and lytic replication. During latency EBV expresses a limited number of viral genes that are involved in tasks such as stimulating cell proliferation, inhibiting apoptosis, blocking viral lytic replication, and assuring accura...

متن کامل

Chemotherapy induces lytic EBV replication and confers ganciclovir susceptibility to EBV-positive epithelial cell tumors.

EBV is an oncogenic herpesvirus associated with a number of human malignancies. The consistent presence of the EBV genome in certain tumors offers the potential for novel EBV-targeted therapies. EBV can infect cells in either a latent or lytic form. Here we demonstrate that a variety of chemotherapeutic agents, including cis-platinum, 5-fluorouracil (5-FU), and taxol, induce the switch from the...

متن کامل

Analysis of Epstein Barr Virus Genome in Serum and Ocular Samples of Patients with Inflammatory Eye Disease Using PCR Method

Background and Aims: Epstein-Barr virus (EBV) infection is very common in the population. Virus belongs to the family Herpesviridae, whose representatives are characterized by the ability to cause the human body latent persistent infections. The goal of this study was to assess EBV infection frequency using PCR method in samples from inflammatory eye disease, in comparison with EBV presence in ...

متن کامل

In vivo dynamics of EBNA1-oriP interaction during latent and lytic replication of Epstein-Barr virus.

The Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is required for maintenance of the viral genome DNA during the latent phase of EBV replication but continues to be synthesized after the induction of viral productive replication. An EBV genome-wide chromatin immunoprecipitation assay revealed that EBNA1 constantly binds to oriP of the EBV genome during not only latent but also lytic infect...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Proceedings of the National Academy of Sciences of the United States of America

دوره 112 52  شماره 

صفحات  -

تاریخ انتشار 2015