N6-Methyladenosine RNA Modification in Inflammation: Roles, Mechanisms, and Applications

Luo, Jun; Xu, Tao; Sun, Kai

doi:10.3389/fcell.2021.670711

Cited by 68 publications

(57 citation statements)

References 137 publications

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“…In recent years, a large number of studies have focused on the role of RNA modifications in regulating inflammation and anti-inflammatory gene expression. Among them, m6A modification may affect the states of various inflammatory diseases through a variety of mechanisms ( 38 ). For example, studies showed that m6A binding protein YTHDF2 could regulate the stability of inflammatory gene mRNA transcripts and participate in the regulation of lipopolysaccharide (LPS)-induced inflammation ( 39 ).…”

Section: Discussionmentioning

confidence: 99%

A genome-wide association analysis: m6A-SNP related to the onset of oral ulcers

Lin²,

Yuan³

et al. 2022

Front. Immunol.

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Oral ulcers are one of the most common inflammatory diseases on oral mucosa that have obvious impacts on patients. Studies have shown that N6-methyladenosine (m6A) RNA transcription modification may be involved in the development of various inflammatory responses, and whether the pathogenesis of oral ulcers is related to m6A is unclear. This study aims to identify how m6A-related single nucleotide polymorphisms (m6A-SNPs) may affect oral ulcers. The UKBB dataset containing 10,599,054 SNPs was obtained from the GWAS database using the keyword “oral ulcer” and compared with the M6AVar database containing 13,703 m6A-SNPs.With 7,490 m6A-SNPs associated with oral ulcers identified, HaploReg and RegulomeDB were used for further functional validation and differential gene analysis was performed using the GEO database dataset GSE37265. A total of 7490 m6A-SNPs were detected in this study, 11 of which were related to oral ulcers (p<5E-08), and all of these SNPs showed eQTL signals. The SNP rs11266744 (p=2.00E-27) may regulate the expression of the local gene CCRL2, thereby participating in the pathogenesis of oral ulcers. In summary, by analyzing genome-wide association studies, this study showed that m6A modification may be involved in the pathogenesis of oral ulcers and CCRL2 may be the targeted gene.

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Section: Discussionmentioning

confidence: 99%

A genome-wide association analysis: m6A-SNP related to the onset of oral ulcers

Lin²,

Yuan³

et al. 2022

Front. Immunol.

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“…We observed significant hypermethylation in end-stage tissue from ALS patients compared to age-matched controls; although we do not believe age is responsible for the observed RNA hypermethylation, other factors may be playing a part. Since astrocytosis and microgliosis are common features of ALS as well as other neurodegenerative diseases, it is possible that much of the observed RNA hypermethylation arises not because of a primary disease mechanism, but instead because of secondary neuroinflammation 76 .…”

Section: Discussionmentioning

confidence: 99%

“…Since astrocytosis and microgliosis are common features of ALS as well as other neurodegenerative diseases, it is possible that much of the observed RNA hypermethylation arises not because of a primary disease mechanism, but instead because of secondary neuroinflammation 76 .…”

Section: Discussionmentioning

confidence: 99%

RNA methylation influences TDP43 binding and disease pathogenesis in models of amyotrophic lateral sclerosis and frontotemporal dementia

McMillan

Gómez

Bekier

et al. 2022

Preprint

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Methylation of RNA at the N6 position of adenosine (m6A) is one of the most common RNA modifications, impacting RNA stability as well as its transport and translation. Previous studies uncovered RNA destabilization in models of amyotrophic lateral sclerosis (ALS), in association with accumulation of the RNA-binding protein TDP43, which is itself mislocalized from the nucleus in >95% of those with ALS. Here, we show that TDP43 recognizes m6A-modified RNA, and that RNA methylation is critical for both TDP43 binding and autoregulation. We also observed extensive hypermethylation of coding and non-coding transcripts in ALS spinal cord, many of which overlap with methylated TDP43 target RNAs. Emphasizing the importance of m6A for TDP43 binding and function, we identified several m6A factors that enhance or suppress TDP43-mediated toxicity via a single-cell CRISPR/Cas9 candidate-based screen in primary neurons. The most promising genetic modifier among these-the canonical m6A reader YTHDF2-accumulated within spinal motor neurons in ALS postmortem sections, and its knockdown prolonged the survival of human neurons carrying ALS-associated mutations. Collectively, these data show that m6A modifications modulate RNA binding by TDP43, and that m6A is pivotal for TDP43-related neurodegeneration in ALS.

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“…Therefore, alterations in RNA m 6 A methylation status can lead to cell dysfunction and disease [ 12 ]. Recent studies have revealed that the m 6 A modification not only has a strong and intricate relationship with cardiovascular disease but may regulate also the inflammatory response arising during different physiopathological conditions [ 13 , 14 ]. Although the clinical significance of m 6 A profiling in sepsis patients has been recently suggested [ 11 ], there is a clear need for studies addressing the specific m 6 A alterations occurring in tissues and organs affected by sepsis.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide identification of altered RNA m6A profiles in vascular tissue of septic rats

Shen

Yao

Nie

et al. 2021

Aging

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Sepsis is the leading cause of death in hospital intensive care units. In light of recent studies showing that variations in N 6 -methyladenosine (m 6 A) levels in different RNA transcripts influence inflammatory responses, we evaluated the m 6 A profiles of rat aortic mRNAs and lncRNAs after lipopolysaccharide (LPS)-induced sepsis. LC-MS-based mRNA modification analysis showed that global m6A levels were significantly decreased in aortic tissue of rats injected intraperitoneally with LPS. This finding was consistent with downregulated expression of METTL3 and WTAP, two members of the m 6 A writer complex, in LPS-exposed aortas. Microarray analysis of m 6 A methylation indicated that 40 transcripts (31 mRNAs and 9 lncRNAs) were hypermethylated, while 223 transcripts (156 mRNAs and 67 lncRNAs) were hypomethylated, in aortic tissue from LPS-treated rats. On GO and KEGG analyses, ‘complement and coagulation cascades’, ‘transient receptor potential channels’, and ‘organic anion transmembrane transporter activity’ were the major biological processes modulated by the differentially m 6 A methylated mRNAs. In turn, competing endogenous RNA network analysis suggested that decreased m 6 A levels in lncRNA-XR_343955 may affect the inflammatory response through the cell adhesion molecule pathway. Our data suggest that therapeutic modulation of the cellular m 6 A machinery may be useful to preserve vascular integrity and function during sepsis.

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N6-Methyladenosine RNA Modification in Inflammation: Roles, Mechanisms, and Applications

Cited by 68 publications

References 137 publications

A genome-wide association analysis: m6A-SNP related to the onset of oral ulcers

A genome-wide association analysis: m6A-SNP related to the onset of oral ulcers

RNA methylation influences TDP43 binding and disease pathogenesis in models of amyotrophic lateral sclerosis and frontotemporal dementia

Genome-wide identification of altered RNA m6A profiles in vascular tissue of septic rats

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