Biological roles of adenine methylation in RNA

Abstract RNA modifications have become hot topics recently. By influencing RNA processes, including generation, transportation, function, and metabolization, they act as critical regulators of cell biology. The immune cell abnormality in human diseases is also a research focus and progressing rapidly these years. Studies have demonstrated that RNA modifications participate in the multiple biological processes of immune cells, including development, differentiation, activation, migration, and polarization, thereby modulating the immune responses and are involved in some immune related diseases. In this review, we present existing knowledge of the biological functions and underlying mechanisms of RNA modifications, including N 6 -methyladenosine (m 6 A), 5-methylcytosine (m 5 C), N 1 -methyladenosine (m 1 A), N 7 -methylguanosine (m 7 G), N 4 -acetylcytosine (ac 4 C), pseudouridine (Ψ), uridylation, and adenosine-to-inosine (A-to-I) RNA editing, and summarize their critical roles in immune cell biology. Via regulating the biological processes of immune cells, RNA modifications can participate in the pathogenesis of immune related diseases, such as cancers, infection, inflammatory and autoimmune diseases. We further highlight the challenges and future directions based on the existing knowledge. All in all, this review will provide helpful knowledge as well as novel ideas for the researchers in this area. 

https://www.nature.com/articles/s41392-022-01175-9.pdf

RNA modifications: importance in immune cell biology and related diseases

N6-methyladenosine (m6A) is an abundant internal RNA modification, influencing transcript fate and function in uninfected and virus-infected cells. Installation of m6A by the nuclear RNA methyltransferase METTL3 occurs cotranscriptionally; however, the genomes of some cytoplasmic RNA viruses are also m6A-modified. How the cellular m6A modification machinery impacts coronavirus replication, which occurs exclusively in the cytoplasm, is unknown. Here we show that replication of SARS-CoV-2, the agent responsible for the COVID-19 pandemic, and a seasonal human β-coronavirus HCoV-OC43, can be suppressed by depletion of METTL3 or cytoplasmic m6A reader proteins YTHDF1 and YTHDF3 and by a highly specific small molecule METTL3 inhibitor. Reduction of infectious titer correlates with decreased synthesis of viral RNAs and the essential nucleocapsid (N) protein. Sites of m6A modification on genomic and subgenomic RNAs of both viruses were mapped by methylated RNA immunoprecipitation sequencing (meRIP-seq). Levels of host factors involved in m6A installation, removal, and recognition were unchanged by HCoV-OC43 infection; however, nuclear localization of METTL3 and cytoplasmic m6A readers YTHDF1 and YTHDF2 increased. This establishes that coronavirus RNAs are m6A-modified and host m6A pathway components control β-coronavirus replication. Moreover, it illustrates the therapeutic potential of targeting the m6A pathway to restrict coronavirus reproduction.

/pdf/targeting-the-m-6-a-rna-modification-pathway-blocks-sars-cov-4gj87r14ad.pdf

Targeting the m 6 A RNA modification pathway blocks SARS-CoV-2 and HCoV-OC43 replication.

The epitranscriptome toolbox

Hepatitis B virus (HBV) is a DNA virus with a complex life cycle that includes a reverse transcription step. HBV is poorly sensed by the immune system and frequently establishes persistent infection that can cause chronic infection, the leading cause of liver cancer and cirrhosis worldwide. Recent mounting evidence has indicated the growing importance of RNA methylation (m6A modification) in viral replication, immune escape, and carcinogenesis. The value of m6A RNA modification for the prediction and clinical management of chronic HBV infection remains to be assessed. However, a number of studies indicate the important role of m6A-marked transcripts and factors of m6A machinery in managing HBV-related pathologies. In this review, we discuss the fundamental and potential clinical impact of m6A modifications on HBV infection and pathogenesis, as well as highlight the important molecular techniques and tools that can be used for studying RNA m6A methylome.

https://www.tandfonline.com/doi/pdf/10.1080/22221751.2021.2006580

Host-cell interactions in HBV infection and pathogenesis: the emerging role of m6A modification.

Double-stranded RNA (dsRNA) is a virus-encoded signature capable of triggering intracellular Rig-like receptors (RLR) to activate antiviral signaling, but whether intercellular dsRNA structural reshaping mediated by the N6-methyladenosine (m6A) modification modulates this process remains largely unknown. Here, we show that, in response to infection by the RNA virus Vesicular Stomatitis Virus (VSV), the m6A methyltransferase METTL3 translocates into the cytoplasm to increase m6A modification on virus-derived transcripts and decrease viral dsRNA formation, thereby reducing virus-sensing efficacy by RLRs such as RIG-I and MDA5 and dampening antiviral immune signaling. Meanwhile, the genetic ablation of METTL3 in monocyte or hepatocyte causes enhanced type I IFN expression and accelerates VSV clearance. Our findings thus implicate METTL3-mediated m6A RNA modification on viral RNAs as a negative regulator for innate sensing pathways of dsRNA, and also hint METTL3 as a potential therapeutic target for the modulation of anti-viral immunity.

/pdf/n6-methyladenosine-rna-modification-suppresses-antiviral-36twbzn36v.pdf

N6-methyladenosine RNA modification suppresses antiviral innate sensing pathways via reshaping double-stranded RNA.

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N6-methyladenosine RNA modification suppresses antiviral innate sensing pathways via reshaping double-stranded RNA.