Epitranscriptomic RNA modifications
Genome sequence maps have guided and vastly expanded our understanding of virus-host interactions. However, the outcome of viral infections is subject to additional levels of regulation not directly encoded in the viral genome sequence per se. One example is epitranscriptomic RNA modifications, such as N6-methyladenosine (m6A), where covalent modifications added to individual nucleotides on an RNA can regulate RNA metabolism and function, mostly through the recruitment or dismissal of functional RNA binding proteins. We believe that viruses have evolved to enrich for RNA modifications that are beneficial to viral replication. Indeed, the RNA base methylation, m6A, can enhance the replication of Human Immunodeficiency virus 1 (HIV-1), Influenza A virus (IAV), and Simian virus 40 (SV40). These observations have been further expanded to modifications on cytidine: where 5-methylcytidine (m5C) and N4-acetylcytidine (ac4C) can enhance, respectively, the translation and stability of HIV-1 transcripts. Modifications, including m6A and pseudouridine, can also prevent modified RNA from activating innate immune responses, as demonstrated on the recent mRNA-based SARS-CoV-2 vaccines. Thus, RNA modifications clearly impact viral infections. However, it remains unclear how modifications such as m5C and ac4C impact viruses other than HIV-1; while the mechanisms of modification-dependent regulation of RNA stability and immune evasion remains largely unclear. The Tsai lab aims to elucidate these unexplored areas of viral RNA modifications, and how they impact virus-host interactions, focusing on Influenza A virus and HIV-1 as our model systems of interest, with future plans to expand into Epstein-Barr virus.
近來研究進展發現核糖核酸(RNA)上的小分子修飾對於RNA的各種功能有十分重要的調控作用，這被稱為RNA表觀遺傳學 (epitranscriptomics)。RNA修飾在病毒的感染與複製過程中扮演著重要的角色。RNA中的腺嘌呤上的甲基化修飾 (m6A) 可增進人類免疫缺乏病毒 (HIV-1)、流感A病毒 (IAV) 等多種病毒的複製; 而RNA核糖鏈的甲基化 (Nm)和m6A甲基化皆可防止病毒的RNA被宿主細胞的先天免疫偵測到。此外，我們也發現胞嘧啶上的甲基化與乙醯化修飾(m5C & ac4C)也可以分別促進HIV-1病毒基因的轉譯與RNA之穩定。以上皆顯示 RNA修飾對病毒感染與複製的過程有著重要的影響。不過，以上多種RNA修飾對HIV-1以外之病毒的調控與機制還有許多未知之處。因次，本實驗室將針對流感A病毒 (IAV) 和HIV-1去了解RNA修飾對這些病毒的感染與致病機制有何影響，進而提供未來對抗病毒的潛在新途徑。未來也計畫拓展領域到跟鼻咽癌、白血病與胃癌相關的Epstein-Barr virus (EBV)病毒。