Global profiling reveals common and distinct N6-methyladenosine (m6A) regulation of innate immune responses during bacterial and viral infections

Abstract

N6-methyladenosine (m6A) is a dynamic post-transcriptional RNA modification influencing all aspects of mRNA biology. While m6A modifications during numerous viral infections have been described, the role of m6A in innate immune response remains unclear. Here, we examined cellular m6A epitranscriptomes during infections of Pseudomonas aeruginosa and herpes simplex virus type 1 (HSV-1), and lipopolysaccharide (LPS) stimulation to identify m6A-regulated innate immune response genes. We showed that a significant portion of cellular genes including many innate immune response genes underwent m6A modifications in 5'UTR and 3'UTR. We identified common and distinct m6A-modified genes under different stimulating conditions. Significantly, the expression of a subset of innate immune response genes was positively correlated with m6A level. Importantly, we identified genes that had significant enrichments of m6A peaks during P. aeruginosa infection following knockdown of m6A “eraser” ALKBH5, confirming the regulation of these genes by m6A and ALKBH5. Among them, we confirmed the association of m6A modification with gene expression in immune response genes TNFAIP3, IFIT1, IFIT2 and IFIH1. Taken together, our results revealed the vital role of m6A in regulating innate immunity against bacterial and viral infections. These works also provided rich resources for the scientific community.

N6-methyladenosine (m6A) and reader protein YTHDF2 enhance innate immune response by mediating DUSP1 mRNA degradation and activating mitogen-activated protein kinases during bacterial and viral infections

“…The copyright holder for this preprint this version posted December 2, 2022. ; https://doi.org/10.1101/2022.12.01.518805 doi: bioRxiv preprint infection. We have previously mapped the cellular expression profiles and m 6 A epitranscriptomes, and identified a set of genes including innate immune response genes that are differentially methylated and differentially expressed during viral and bacterial infections (13). Among them, DUSP1, an important regulator of innate immune response genes, was significantly hyper-methylated during gram-negative bacteria Pseudomonas aeruginosa infection, which peaked at 2 h post-infection (hpi), then decreased at 4 and 6 hpi (Fig.…”

“…m 6 A-immunoprecipitation (m 6 A-IP). Isolation of m 6 A-containing fragments was performed as previously described (13,36). Briefly, total RNA was extracted from cells using TRI Reagent (T9424-200ML, Sigma-Aldrich) and fragmented using RNA fragmentation kit (AM8740, ThermoFisher).…”

“…N6-methyladenosine (m 6 A), a dynamic posttranscriptional RNA modification, is critical for almost all aspects of RNA metabolism and functions including structure, maturation, stability, splicing, export, translation, and decay (12). Recent studies show that m 6 A modification not only directly regulates the expression of innate immune response genes, but also indirectly affects the mRNA metabolism pathway to further regulate the innate immune response during bacterial and viral infections (13)(14)(15)(16) .…”

METTL3 Attenuates Inflammation in Fusarium solani–Induced Keratitis via the PI3K/AKT Signaling Pathway

“…In addition to playing a prominent role in many physiological processes, m 6 A modification contributes to immune responses following microbial infections. 28 – 30 Several components contribute to the regulation of m 6 A methylation. These include methyltransferases, demethylases, and binding proteins.…”

Gene signature of m6A RNA regulators in diagnosis, prognosis, treatment, and immune microenvironment for cervical cancer

“…Patients in cluster 1 had higher m 6 AScores and worse prognosis, whereas patients in cluster 2 had the exact opposite. In recent years, it has been reported in the literature that m 6 A regulators can participate in regulating the occurrence, development, and treatment of various tumors by affecting immune-related processes, including but not limited to immune response 45 , 46 , immune checkpoint expression 47 , 48 , and immune escape 49 , 50 . Immune cell infiltration analysis and tumor microenvironment analysis clarified that the immune status and microenvironment were significantly different in m 6 AScore groups.…”