Recent reports have highlighted how SARS-CoV-2 infection and the resulting COVID-19 can turn epigenetics against us; however, new research now reveals that the epigenetic machinery can also help us fight back against viral attacks – in the guise of specific RNA modifications.
A team of epigenetic tusslers guided by Yu Chen (Wuhan University) knew of a squadron of studies reporting that the N6-methyladenosine (m6A) RNA modification plays a critical regulatory role in the SARS-CoV-2 life cycle; however, they realized that the relevance of the all-important 5-methylcytosine (m5C) RNA modification remained somewhat unexplored for SARS-CoV-2 and viruses in general. This knowledge gap prompted the profiling of m5C in SARS-CoV-2 RNA and an exploration of how this RNA modification regulates viral replication/pathogenesis. Fascinatingly, they now report that human cells fight back against SARS-CoV-2 infection by inducing the m5C modification of viral RNA.
Let’s hear more from Wang, Feng, and Colleagues on how an RNA modification helps to fight back against SARS-CoV-2:
- Liquid chromatography with tandem mass spectrometry (LC-MS/MS) reveals the more abundant nature of m5C in viral RNA compared to m6A
- Meanwhile, m5C-methylated RNA immunoprecipitation sequencing (m5C-MeRIP-seq) supports the profiling of the m5C landscape of viral RNA
- While the knockdown of m6A methyltransferases mildly increases viral replication, the knockdown of the m5C methyltransferase NSUN2 prompts a reduction in m5C levels on viral RNA and enhances viral replication
- These findings provide evidence for NSUN2 as a negative regulator of viral replication
- Combined RNA bisulfite sequencing (RNA-BisSeq) and m5C-MeRIP-seq identify NSUN2-dependent m5C-methylated cytosines distributed across positive-sense genomic viral RNA
- Fascinatingly, mutations of the identified cytosines enhance viral RNA stability, suggesting that the m5C modification of viral RNA facilitates degradation
- Nsun2-deficient mice exhibit higher viral burden and more severe lung tissue damage
- Progeny SARS-CoV-2 virions from Nsun2-deficient mice with low m5C levels also exhibit a stronger replication ability
These exciting findings suggest that epigenetic machinery “fights back” with RNA modifications when facing the dastardly enemy that is the SARS-CoV-2 virus. Overall, the authors suggest the more critical nature of NSUN2-mediated m5C modification compared to m6A in the regulation of viral replication and virulence/pathogenesis – a fact that could represent the starting point for the development of new anti-coronavirus drugs or related therapeutic interventions.
For more on how epigenetic machinery fights back against viral attacks via RNA modifications, see Science Advances, August 2024.