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Ten-eleven translocation (Tet) methylcytosine dioxygenase-dependent viral DNA demethylation mediates in vivo hepatitis B virus (HBV) biosynthesis

journal contribution
posted on 2025-02-03, 14:36 authored by Rachel Matrenec, Claudia E. Oropeza, Eddie Dekoven, Grant Tarnow, Mark Maienschein-Cline, Cecilia S. Chau, Stefan Green, Alan McLachlanAlan McLachlan

Liver-specific ten-eleven translocation (Tet) methylcytosine dioxygenases 2 and 3 (Tet2 plus Tet3)-deficient hepatitis B virus (HBV) transgenic mice fail to support viral biosynthesis. The levels of viral transcription and replication intermediates are dramatically reduced. Hepatitis B core antigen is only observed in a very limited number of pericentral hepatocytes in a pattern that is similar to glutamate-ammonia ligase (Glul), a β-catenin target gene. HBV transcript abundance in adult Tet-deficient deficientTet-deficientmice resembles that observed in wild-type neonatal mice. Furthermore, the RNA levels of several β-catenin target genes including Glul, Lhpp, Notun, Oat, Slc1a2, and Tbx3 in Tet-deficient mice were also similar to that observed in wild-type neonatal mice. As HBV transcription is regulated by β-catenin, these findings support the suggestion that neonatal Tet deficiency might limit β-catenin target gene expression, limiting viral biosynthesis. Additionally, HBV transgene DNA displays increased 5-methylcytosine (5mC) frequency at CpG sequences consistent with neonatal Tet deficiency being responsible for decreased developmental viral DNA demethylation mediated by 5mC oxidation to 5-hydroxymethylcytosine, a process that might be responsible for the reduction in cellular β-catenin target gene expression and viral transcription and replication.

Funding

NIAID R01 AI170785 (AMcL)

NCI R01 CA238328 (AMcL)

NCATS UL1TR002003 (MMC)

History

Citation

Ten-eleven translocation (Tet) methylcytosine dioxygenase-dependent viral DNA demethylation mediates in vivo hepatitis B virus (HBV) biosynthesis. Matrenec R, Oropeza CE, Dekoven E, Tarnow G, Maienschein-Cline M, Chau CS, Green SJ, McLachlan A. J Virol. 2024 Feb 20;98(2):e0172123. 10.1128/jvi.01721-23.

Publisher

American Society for Microbiology.

Language

  • en_US

issn

Print version: ISSN: 0022-538X Electronic version: ISSN: 1098-5514

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