m6A Modification Mediates Mucosal Immune Microenvironment and Therapeutic Response in Inflammatory Bowel Disease

Chen, Yongyu; Lei, Jing; He, Song

doi:10.3389/fcell.2021.692160

Cited by 24 publications

(27 citation statements)

References 48 publications

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“…M6A is a ubiquitous RNA modification that plays a vital role in human tumors ( 27 ). A study showed that M6A-related genes were dysregulated in CRC, and their expression was associated with CRC progression and poor prognosis ( 28 ). Moreover, FTO gene may have a key role in mucosal immune health ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

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The effect of FTO rs9939609 polymorphism on the association between colorectal cancer and dietary fiber

et al. 2022

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BackgroundGene polymorphisms may explain the controversy on the association between colorectal cancer (CRC) and dietary fibers. The purpose of this study was to investigate the effect of fat mass and obesity-associated (FTO) rs9939609 polymorphism on the association between colorectal cancer and dietary fiber.MethodsThis case-control study was conducted on 160 CRC cases and 320 healthy controls in Tehran, Iran. The participants' food intake was assessed using a semi-quantitative food frequency questionnaire (FFQ). The frequency of rs9939609 FTO polymorphism in the case and control groups was determined using the tetra-primer amplification refractory mutation (tetra-ARMS) method.ResultsIn the participants with the TT genotype of the FTO rs9939609, the cases had higher BMI and lower intake of dietary fiber compared to the controls (P = 0.01). Among A allele carriers of FTO rs9939609 polymorphism, the cases had higher BMI (P = 0.04) and lower intake of total fiber (P = 0.02) and soluble fiber (P = 0.02). An inverse association was found between CRC and dietary fiber intake among those with the AA/AT FTO rs9939609 genotype after adjusting for age, sex, smoking, alcohol consumption, physical activity, BMI, and calorie intake (OR = 0.9, CI 95%:0.84–0.92, P < 0.05).ConclusionThis study found a link between higher dietary fiber consumption and a lower risk of CRC in A-allele carriers of FTO rs9939609 polymorphism. Future studies are needed to identify the underlying mechanisms of the association between CRC and dietary fibers in people with different FTO genotypes.

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Section: Discussionmentioning

confidence: 99%

“…Moreover, FTO gene may have a key role in mucosal immune health ( 27 ). A recent study found that m6A modification may affect immune infiltration and therapeutic response in inflammatory bowel disease (IBD) ( 28 ).…”

Section: Discussionmentioning

confidence: 99%

The effect of FTO rs9939609 polymorphism on the association between colorectal cancer and dietary fiber

et al. 2022

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“…44 More importantly, a recent study by Chen et al emphasized the importance of the m6A modification in regulating the immune infiltration and therapeutic response in inflammatory bowel disease. 45 These findings suggested that m6A modification plays important role in the pathogenesis of intestinal-related diseases. As far as we know, no report has elucidated the role of METTL3-mediated m6A modification in functional constipation.…”

Section: Discussionmentioning

confidence: 95%

METTL3 contributes to slow transit constipation by regulating miR‐30b‐5p/PIK3R2/Akt/mTOR signaling cascade through DGCR8

Gong

Dai

et al. 2022

J of Gastro and Hepatol

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Background N6‐methyladenosine (m6A) is the most prevalent methylation modification of eukaryotic RNA, and methyltransferase‐like 3 (METTL3) plays a vital role in multiple cell functions. This study aimed to investigate the role of m6A methylase METTL3 in slow transit constipation (STC). Material and Method The expression of METTL3 and DGCR8 was measured in STC tissues and glutamic acid‐induced interstitial cells of Cajal (ICCs). The effects of METTL3, miR‐30b‐5p, and DGCR8 on the biological characteristics of ICCs were investigated on the basis of loss‐of‐function analyses. Luciferase reporter assay was used to identify the direct binding sites of miR‐30b‐5p with PIK3R2. Results The results showed that the METTL3, DGCR8, miR‐30b‐5p, and the methylation level of m6A were significantly increased in STC tissues and glutamic acid‐induced ICCs. Silencing of METTL3 and miR‐30b‐5p inhibited apoptosis, autophagy, and pyroptosis of glutamic acid‐induced ICCs. Moreover, overexpression of miR‐30b‐5p reversed the cytoprotection of METTL3 knockdown in glutamic acid‐induced ICCs. Besides, DGCR8 knockdown could facilitate cell growth and decrease apoptotic glutamic acid‐induced ICCs. Mechanically, we illustrated that METTL3 in glutamic acid‐induced ICCs significantly accelerated the maturation of pri‐miR‐30b‐5p by m6A methylation modification, resulting in the reduction of PIK3R2, which results in the inhibition of PI3K/Akt/mTOR pathway and ultimately leads to the cell death of STC. Conclusions Collectively, these data demonstrated that METTL3 promoted the apoptosis, autophagy, and pyroptosis of glutamic acid‐induced ICCs by interacting with the DGCR8 and successively modulating the miR‐30b‐5p/PIK3R2 axis in an m6A‐dependent manner, and METTL3 may be a potential therapeutic target for STC.

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“…In addition, increasing studies have reported a role for type I IFNs (interferons) in the pathogenesis of different subsets of RA patients, indicating that IFN-a/bactivity may have essential clinical utility in predicting response to tumor necrosis factor antagonists (35-37). Chen et al also found that the expression of m6A phenotype-related hub genes might predict a therapeutic response to anti-TNF therapy in inflammatory bowel disease (38). Previous studies have demonstrated that m6A involves the progression of the inflammatory response by affecting TNF-a degradation and regulation.…”

Section: Discussionmentioning

confidence: 97%

“…Chen et al. also found that the expression of m6A phenotype-related hub genes might predict a therapeutic response to anti-TNF therapy in inflammatory bowel disease ( 38 ). Previous studies have demonstrated that m6A involves the progression of the inflammatory response by affecting TNF-α degradation and regulation.…”

Section: Discussionmentioning

confidence: 99%

Predictive value of drug efficacy by M6A modification patterns in rheumatoid arthritis patients

et al. 2022

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BackgroundRheumatoid arthritis is a highly heterogeneous autoimmune disease characterized by unpredictable disease flares and significant differences in therapeutic response to available treatments. One possible reason for poor efficacy is that it cannot be treated accurately due to no optimal stratification for RA patients.ObjectiveThis study aims to construct an RA classification model by m6A characters and further predict response to medication.MethodsTwenty m6A regulators were used to construct a random forest diagnosis model, and RNA-seq analysis was employed for external validation. The RNA modification patterns mediated by 20 m6A regulators were systematically evaluated in 1191 RA samples and explored different molecular clusters associated with other immune microenvironment characteristics and biological pathways. Then, we established an m6A score model to quantify the m6A modification patterns. The model was applied to patients at baseline to test the association between m6Ascore and infliximab responsiveness.ResultsThe m6A diagnosis model showed good discriminatory ability in distinguishing RA. Patients with RA were classified into three clusters with distinct molecular and cellular signatures. Cluster A displayed strongly activated inflammatory cells and pathways. Specific innate lymphocytes occupied cluster B. Cluster C was mainly enriched in prominent adaptive lymphocytes and NK-mediated cytotoxicity signatures with the highest m6A score. Patients with a low m6Ascore exhibited significantly infliximab therapeutic benefits compared with those with a high m6Ascore (p< 0.05).ConclusionOur study is the first to provide a comprehensive analysis of m6A modifications in RA, which provides an innovative patient stratification framework and potentially enables improved therapeutic decisions.

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m6A Modification Mediates Mucosal Immune Microenvironment and Therapeutic Response in Inflammatory Bowel Disease

Cited by 24 publications

References 48 publications

The effect of FTO rs9939609 polymorphism on the association between colorectal cancer and dietary fiber

The effect of FTO rs9939609 polymorphism on the association between colorectal cancer and dietary fiber

METTL3 contributes to slow transit constipation by regulating miR‐30b‐5p/PIK3R2/Akt/mTOR signaling cascade through DGCR8

Predictive value of drug efficacy by M6A modification patterns in rheumatoid arthritis patients

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