An alternative splicing signature in human Crohn\u2019s disease

Daowei Li,Daowei Li,Jia Lu,Yue Tan,Yuanzi Liang,Yuanzi Liang

doi:10.1186/s12876-021-02001-2

Daowei Li, Daowei Li + Show 4 more

Open Access

https://doi.org/10.1186/s12876-021-02001-2

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Abstract

BackgroundAlthough hundreds of risk loci for Crohn’s disease (CD) have been identified, the underlying pathogenesis of CD remains unclear. Recently, evidence has shown that aberrant gene expression in colon tissues of CD patients is associated with the progression of CD. We reasoned that post-transcriptional regulation, especially alternative splicing (AS), may also play important roles in the pathogenesis of CD.MethodsWe re-analyzed public mRNA-seq data from the NCBI GEO dataset (GSE66207) and identified approximately 3000 unique AS events in CD patients compared to healthy controls.Results“Lysine degradation” and “Sphingolipid metabolism” were the two most enriched AS events in CD patients. In a validation study, we also sequenced eight subjects and demonstrated that key genes that were previously linked to CD, such as IRF1 and STAT3, also had significant AS events in CD.ConclusionOur study provided a landscape of AS events in CD, especially as the first study focused on a Chinese cohort. Our data suggest that dysregulation of AS may be a new mechanism that contributes to the pathogenesis of CD.

Highlights

Hundreds of risk loci for Crohn’s disease (CD) have been identified, the underlying pathogenesis of CD remains unclear
Splicing types In the study of identifying alternative splicing (AS) events in the data from GSE66207, we found eight types of AS events, including alternative 3’ splice site (A3SS), alternative 5’splice site, alternative first exon (AFE), alternative last exon, mutually exclusive exons (MXE), retrained introns (RI), skipped exon (SE), and tandem 3’ Three prime untranslated region (UTR)
We found that eight inflammation-related genes were regulated by CD-related AS events

Summary

Introduction

Hundreds of risk loci for Crohn’s disease (CD) have been identified, the underlying pathogenesis of CD remains unclear. Evidence has shown that aberrant gene expression in colon tissues of CD patients is associated with the progression of CD. We reasoned that post-transcriptional regulation, especially alternative splicing (AS), may play important roles in the pathogenesis of CD. Crohn’s disease (CD), an inflammatory bowel disease (IBD), is thought to be caused by dysregulated mucosal immune responses to the gut flora in genetically susceptible patients [1]. Genome-wide association studies and subsequent meta-analyses could explain the underlying pathophysiology of CD to some extent, the pathogenesis of CD remains unclear. Recent studies have shown that dysregulated gene expression in the gut mucosa of CD patients may determine the initiation and progression of CD [4].

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Discussion

Conclusion