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Widespread remodeling of the m⁶A RNA-modification landscape by a viral regulator of RNA processing and export.

ABSTRACT: N ⁶-methyladenosine (m⁶A) is the most abundant internal messenger RNA (mRNA) modification, contributing to the processing, stability, and function of methylated RNAs. Methylation occurs in the nucleus during pre-mRNA synthesis and requires a core methyltransferase complex consisting of METTL3, METTL14, and WTAP. During herpes simplex virus (HSV-1) infection, cellular gene expression is profoundly suppressed, allowing the virus to monopolize the host transcription and translation apparatus and antagonize antiviral responses. The extent to which HSV-1 uses or manipulates the m⁶A pathway is not known. Here, we show that, in primary fibroblasts, HSV-1 orchestrates a striking redistribution of the nuclear m⁶A machinery that progresses through the infection cycle. METTL3 and METTL14 are dispersed into the cytoplasm, whereas WTAP remains nuclear. Other regulatory subunits of the methyltransferase complex, along with the nuclear m⁶A-modified RNA binding protein YTHDC1 and nuclear demethylase ALKBH5, are similarly redistributed. These changes require ICP27, a viral regulator of host mRNA processing that mediates the nucleocytoplasmic export of viral late mRNAs. Viral gene expression is initially reduced by small interfering RNA (siRNA)-mediated inactivation of the m⁶A methyltransferase but becomes less impacted as the infection advances. Redistribution of the nuclear m⁶A machinery is accompanied by a wide-scale reduction in the installation of m⁶A and other RNA modifications on both host and viral mRNAs. These results reveal a far-reaching mechanism by which HSV-1 subverts host gene expression to favor viral replication.

SUBMITTER: Srinivas KP

PROVIDER: S-EPMC8325250 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The epigenetic modifier N6-methyladenosine (m6A), recognized as the most prevalent internal modification in messenger RNA (mRNA), has recently emerged as a pivotal player in immune regulation. Its dysregulation has been implicated in the pathogenesis of various autoimmune conditions. However, the implications of m6A modification within the immune microenvironment of Sjögren's syndrome (SS), a chronic autoimmune disorder characterized by exocrine gland dysfunction, remain unexplored. Herein, we leverage an integrative analysis combining public database resources and novel sequencing data to investigate the expression profiles of m6A regulatory genes in SS. Our cohort comprised 220 patients diagnosed with SS and 62 healthy individuals, enabling a comprehensive evaluation of peripheral blood at the transcriptomic level. We report a significant association between SS and altered expression of key m6A regulators, with these changes closely tied to the activation of CD4+ T cells. Employing a random forest (RF) algorithm, we identified crucial genes contributing to the disease phenotype, which facilitated the development of a robust diagnostic model via multivariate logistic regression analysis. Further, unsupervised clustering revealed two distinct m6A modification patterns, which were significantly associated with variations in immunocyte infiltration, immune response activity, and biological function enrichment in SS. Subsequently, we proceeded with a screening process aimed at identifying genes that were differentially expressed (DEGs) between the two groups distinguished by m6A modification. Leveraging these DEGs, we employed weight gene co-expression network analysis (WGCNA) to uncover sets of genes that exhibited strong co-variance and hub genes that were closely linked to m6A modification. Through rigorous analysis, we identified three critical m6A regulators - METTL3, ALKBH5, and YTHDF1 - alongside two m6A-related hub genes, COMMD8 and SRP9. These elements collectively underscore a complex but discernible pattern of m6A modification that appears to be integrally linked with SS's pathogenesis. Our findings not only illuminate the significant correlation between m6A modification and the immune microenvironment in SS but also lay the groundwork for a deeper understanding of m6A regulatory mechanisms. More importantly, the identification of these key regulators and hub genes opens new avenues for the diagnosis and treatment of SS, presenting potential targets for therapeutic intervention.

Project description:BackgroundThe role of epigenetic modulation in immunity is receiving increased recognition-particularly in the context of RNA N6-methyladenosine (m6A) modifications. Nevertheless, it is still uncertain whether m6A methylation plays a role in the onset and progression of intracranial aneurysms (IAs). This study aimed to establish the function of m6A RNA methylation in IA, as well as its correlation with the immunological microenvironment.MethodsOur study included a total of 97 samples (64 IA, 33 normal) in the training set and 60 samples (44 IA, 16 normal) in the validation set to systematically assess the pattern of RNA modifications mediated by 22 m6A regulators. The effects of m6A modifications on immune microenvironment features, i.e., immune response gene sets, human leukocyte antigen (HLA) genes, and infiltrating immune cells were explored. We employed Lasso, machine learning, and logistic regression for the purpose of identifying an m6A regulator gene signature of IA with external data validation. For the unsupervised clustering analysis of m6A modification patterns in IA, consensus clustering methods were employed. Enrichment analysis was used to assess immune response activity along with other functional pathways. The identification of m6A methylation markers was identified based on a protein-protein interaction network and weighted gene co-expression network analysis.ResultsWe identified an m6A regulator signature of IGFBP2, IGFBP1, IGF2BP2, YTHDF3, ALKBH5, RBM15B, LRPPRC, and ELAVL1, which could easily distinguish individuals with IA from healthy individuals. Unsupervised clustering revealed three m6A modification patterns. Gene enrichment analysis illustrated that the tight junction, p53 pathway, and NOTCH signaling pathway varied significantly in m6A modifier patterns. In addition, the three m6A modification patterns showed significant differences in m6A regulator expression, immune microenvironment, and bio-functional pathways. Furthermore, macrophages, activated T cells, and other immune cells were strongly correlated with m6A regulators. Eight m6A indicators were discovered-each with a statistically significant correlation with IA-suggesting their potential as prognostic biological markers.ConclusionOur study demonstrates that m6A RNA methylation and the immunological microenvironment are both intricately correlated with the onset and progression of IA. The novel insight into patterns of m6A modification offers a foundation for the development of innovative treatment approaches for IA.

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Widespread remodeling of the m⁶A RNA-modification landscape by a viral regulator of RNA processing and export.

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Dataset Information

Widespread remodeling of the m6A RNA-modification landscape by a viral regulator of RNA processing and export.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Widespread remodeling of the m⁶A RNA-modification landscape by a viral regulator of RNA processing and export.