Infection phase-dependent dynamics of the viral and host N6-methyladenosine epitranscriptome in the lifecycle of an oncogenic virus in vivo. Infection phase-dependent dynamics of the viral and host N6-methyladenosine epitranscriptome in the lifecycle of an oncogenic virus in vivo

Dynamic alteration of the epitranscriptome exerts regulatory effects on the lifecycle of oncogenic viruses in vitro. However, little is known about these effects in vivo because of the general lack of suitable animal infection models of these viruses. Using a model of rapid-onset Marek’s disease lymphoma in chickens, we investigated changes in viral and host mRNA N6-methyladenosine (m6A) modification during Marek’s disease virus (MDV) infection in vivo. We found that the expression of major epitranscriptomic proteins varies among viral infection phases, reprograming both the viral and the host epitranscriptomes.Specifically, the METTL3/14 complex was suppressed during the lytic and reactivation phases of the MDV lifecycle, whereas its expression was increased during the latent phase and in MDV-induced tumors. METTL3/14 overexpression inhibits, whereas METTL3/14 knockdown enhances, MDV gene expression and replication. These findings reveal the dynamic features of the mRNA m6A modification program during viral replication in vivo, especially in relation to key pathways involved in tumorigenesis. Overall design: Using a model of rapid-onset Marek’s disease lymphoma in chickens, we investigated changes in viral and host mRNA N6-methyladenosine (m6A) modification during Marek’s disease virus (MDV) infection in vivo.

表观转录组(epitranscriptome)的动态改变可在体外对致癌病毒的生命周期发挥调控作用。然而，由于目前普遍缺乏适配这类病毒的动物感染模型，人们对其在体内的调控效应仍知之甚少。本研究以鸡的速发性马立克氏病淋巴瘤模型为研究对象，探究了体内马立克氏病病毒(MDV)感染过程中病毒与宿主mRNA N6-甲基腺苷(m6A)修饰的变化情况。研究发现，主要表观转录组蛋白的表达在病毒感染的不同阶段存在差异，进而同时重塑了病毒与宿主的表观转录组。具体而言，MDV生命周期的裂解期与再激活期会抑制METTL3/14复合物的表达，而在潜伏期以及MDV诱导的肿瘤中，该复合物的表达则会上调。过表达METTL3/14会抑制MDV的基因表达与复制，而敲低METTL3/14则会增强这一过程。上述研究结果揭示了体内病毒复制过程中mRNA m6A修饰程序的动态特征，尤其是其与肿瘤发生相关关键通路的关联。整体实验设计：本研究以鸡的速发性马立克氏病淋巴瘤模型为研究对象，探究了体内马立克氏病病毒(MDV)感染过程中病毒与宿主mRNA N6-甲基腺苷(m6A)修饰的变化情况。