1. Oxygen-dependent histone lysine demethylase 4 restricts hepatitis B virus replication.
- Author
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Harris JM, Magri A, Faria AR, Tsukuda S, Balfe P, Wing PAC, and McKeating JA
- Subjects
- Humans, DNA, Viral genetics, Genome, Viral genetics, Hepatitis B enzymology, Hepatitis B metabolism, Hepatitis B virology, Liver enzymology, Liver metabolism, Liver virology, Plasmids genetics, Transcriptome, Hepatitis B virus genetics, Hepatitis B virus growth & development, Hepatitis B virus metabolism, Jumonji Domain-Containing Histone Demethylases metabolism, Oxygen metabolism, Virus Replication genetics
- Abstract
Mammalian cells have evolved strategies to regulate gene expression when oxygen is limited. Hypoxia-inducible factors (HIF) are the major transcriptional regulators of host gene expression. We previously reported that HIFs bind and activate hepatitis B virus (HBV) DNA transcription under low oxygen conditions; however, the global cellular response to low oxygen is mediated by a family of oxygenases that work in concert with HIFs. Recent studies have identified a role for chromatin modifiers in sensing cellular oxygen and orchestrating transcriptional responses, but their role in the HBV life cycle is as yet undefined. We demonstrated that histone lysine demethylase 4 (KDM4) can restrict HBV, and pharmacological or oxygen-mediated inhibition of the demethylase increases viral RNAs derived from both episomal and integrated copies of the viral genome. Sequencing studies demonstrated that KDM4 is a major regulator of the hepatic transcriptome, which defines hepatocellular permissivity to HBV infection. We propose a model where HBV exploits cellular oxygen sensors to replicate and persist in the liver. Understanding oxygen-dependent pathways that regulate HBV infection will facilitate the development of physiologically relevant cell-based models that support efficient HBV replication., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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