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Published on: December 15, 2017
A Broad m6A Modification Landscape in Inflammatory Bowel Disease
Kai Nie1,2, Jun Yi3, Yuanyuan Yang1,2
1Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, China.
Abstract:
Background and Aims: N6-Methyladenosine (m6A) is the most common post-transcriptional modification on eukaryotic mRNA, affecting the mRNA's fate. The role of m6A regulation in inflammatory bowel disease is unclear. Here, we investigated the m6A landscape in inflammatory bowel diseases (IBD). Methods: Eleven human IBD microarray datasets were recruited from the Gene Expression Omnibus database and four were selected as discovery cohorts. An RNA-seq dataset from the Inflammatory Bowel Disease Multi'omics Database was used as a validation cohort. m6A regulators were measured in volunteers' colonic samples. Consensus clustering and immune scoring were used to estimate the characteristics of m6A regulation in IBD. m6A-related characteristics of different sub-phenotypes, sample sources, and biological therapeutic responses were determined using seven independent datasets. Results: m6A modification involves methyltransferases (writers), demethylases (erasers), and methylation-reading proteins (readers). A wide interaction exists between m6A regulators and IBD risk genes. The IBD risk loci can also be modified by m6A modifications in the public m6A sequencing data. Furthermore, m6A regulators displayed extensive differential expression in four independent discovery cohorts that share common differential genes (IGF2BP2, HNRNPA2B1, ZCCHC4, and EIF3I). In the validated cohort and enrolled volunteers' colonic biopsy samples, the differential m6A regulators were reconfirmed. Two clusters of consensus clustering exhibit different immune phenotypes. m6A-modified positions exist in the core IBD immune cytokines. Another set of IBD datasets revealed m6A-related differences across clinical phenotypes, biological samples, and therapeutic response subgroups in IBD patients. Conclusion: Regulation of m6A methylation is widely involved in IBD occurrence and development. m6A modifications in risk variants, core cytokines, immune cells, and other proteins may deeply influence the pathophysiology and clinical phenotypes. Further studies are needed to determine its role in IBD.
Insights
N6-Methyladenosine (m6A) regulation is implicated in inflammatory bowel disease (IBD) development. This study reveals m6A modifications in IBD risk genes and immune cytokines, influencing disease phenotypes.
Area of Science:
- Epigenetics and Molecular Biology
- Gastroenterology and Immunology
Background:
- N6-Methyladenosine (m6A) is the most prevalent mRNA modification, impacting gene expression.
- The specific role of m6A regulation in the pathogenesis of inflammatory bowel diseases (IBD) remains largely uncharacterized.
Purpose of the Study:
- To investigate the m6A RNA methylation landscape in inflammatory bowel diseases.
- To explore the association between m6A regulators, IBD risk genes, and immune responses.
Main Methods:
- Analysis of multiple human IBD microarray and RNA-seq datasets.
- Measurement of m6A regulators in colonic tissue samples.
- Application of consensus clustering and immune scoring to characterize m6A regulation in IBD.
Main Results:
- m6A regulators showed differential expression in IBD cohorts, with common genes identified (IGF2BP2, HNRNPA2B1, ZCCHC4, EIF3I).
- m6A modifications were found in IBD risk loci and core immune cytokines.
- Distinct immune phenotypes and clinical differences were associated with m6A regulation patterns in IBD patients.
Conclusions:
- m6A methylation regulation plays a significant role in the occurrence and development of IBD.
- m6A modifications in genetic risk factors, immune mediators, and proteins likely influence IBD pathophysiology and clinical presentation.
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