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5-hydroxymethylation of the EBV genome regulates the latent to lytic switch.
Proc Natl Acad Sci U S A. 2015 Dec 29; 112(52):E7257-65.PN

Abstract

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.

Authors+Show Affiliations

Department of Medical Microbiology and Immunology, Wisconsin Institutes for Medical Research (WIMR) II, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705;Cellular and Molecular Biology Graduate Program, WIMR II, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705;Department of Oncology, WIMR II, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705;Department of Oncology, WIMR II, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705;Department of Oncology, WIMR II, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705;Department of Oncology, WIMR II, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705;Department of Oncology, WIMR II, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705;Department of Oncology, WIMR II, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705; Department of Medicine, WIMR II, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705.Department of Oncology, WIMR II, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705; Department of Medicine, WIMR II, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705 skenney@wisc.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

26663912

Citation

Wille, Coral K., et al. "5-hydroxymethylation of the EBV Genome Regulates the Latent to Lytic Switch." Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 52, 2015, pp. E7257-65.
Wille CK, Nawandar DM, Henning AN, et al. 5-hydroxymethylation of the EBV genome regulates the latent to lytic switch. Proc Natl Acad Sci U S A. 2015;112(52):E7257-65.
Wille, C. K., Nawandar, D. M., Henning, A. N., Ma, S., Oetting, K. M., Lee, D., Lambert, P., Johannsen, E. C., & Kenney, S. C. (2015). 5-hydroxymethylation of the EBV genome regulates the latent to lytic switch. Proceedings of the National Academy of Sciences of the United States of America, 112(52), E7257-65. https://doi.org/10.1073/pnas.1513432112
Wille CK, et al. 5-hydroxymethylation of the EBV Genome Regulates the Latent to Lytic Switch. Proc Natl Acad Sci U S A. 2015 Dec 29;112(52):E7257-65. PubMed PMID: 26663912.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 5-hydroxymethylation of the EBV genome regulates the latent to lytic switch. AU - Wille,Coral K, AU - Nawandar,Dhananjay M, AU - Henning,Amanda N, AU - Ma,Shidong, AU - Oetting,Kayla M, AU - Lee,Dennis, AU - Lambert,Paul, AU - Johannsen,Eric C, AU - Kenney,Shannon C, Y1 - 2015/12/09/ PY - 2015/12/15/entrez PY - 2015/12/15/pubmed PY - 2016/8/12/medline KW - 5hmC KW - EBV KW - NPC KW - lytic reactivation SP - E7257 EP - 65 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 112 IS - 52 N2 - 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. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/26663912/5_hydroxymethylation_of_the_EBV_genome_regulates_the_latent_to_lytic_switch_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=26663912 DB - PRIME DP - Unbound Medicine ER -