Oxygen-dependent histone lysine demethylase 4 restricts hepatitis B virus replication

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.哺乳动物细胞在氧含量受限的条件下，进化出了调控基因表达的策略。缺氧诱导因子（Hypoxia inducible factors, HIF）是宿主基因表达的主要转录调控因子。我们此前的研究表明，低氧条件下HIF可结合并激活乙型肝炎病毒（hepatitis B virus, HBV）的DNA转录；然而，细胞对低氧的全局应答是由一类与HIF协同作用的加氧酶家族介导的。近期研究已证实染色质修饰因子（chromatin modifiers）在感知细胞氧状态并协调转录应答过程中发挥作用，但其在HBV生命周期中的功能尚未明确。我们的研究证实，组蛋白赖氨酸去甲基化酶4（histone lysine demethylase 4, KDM4）可抑制HBV复制；通过药理学手段或氧介导的去甲基化酶抑制，可增加源自病毒基因组游离型与整合型拷贝的病毒RNA水平。测序研究表明，KDM4是肝脏转录组的核心调控因子，其可决定肝细胞对HBV感染的易感性。我们提出了一个模型：HBV可利用细胞氧感知通路实现在肝脏内的复制与持续感染。阐明调控HBV感染的氧依赖性通路，将有助于开发支持高效HBV复制的生理相关细胞模型。