Altered splicing associated with the pathology of inflammatory bowel disease

Kiera Berger,Greg Gibson,Jarod Prince,Hari Somineni,Subra Kugathasan

doi:10.1186/s40246-021-00347-y

Kiera Berger, Greg Gibson + Show 3 more

Open Access

https://doi.org/10.1186/s40246-021-00347-y

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Journal: Human genomics	Publication Date: Jul 23, 2021
Citations: 8	License type: open-access

Affiliation: Georgia Institute of Technology, Emory University

Abstract

BackgroundAberrant splicing of individual genes is a well-known mechanism promoting pathology for a wide range of conditions, but disease is less commonly attributed to global disruption of exon usage. To explore the possible association of aberrant splicing with inflammatory bowel disease, we developed a pipeline for quantifying transcript abundance and exon inclusion transcriptome-wide and applied it to a dataset of ileal and rectal biopsies, both obtained in duplicate from 34 pediatric or young adult cases of ulcerative colitis and Crohn’s disease.ResultsExpression and splicing covary to some extent, and eight individuals exhibited aberrant profiles that can be explained by altered ratios of epithelial to stromal and immune cells. Ancestry-related biases in alternative splicing accounting for 5% of the variance were also observed, in part also related to cell-type proportions. In addition, two individuals were identified who had 284 exons with significantly divergent percent spliced in exons, including in the established IBD risk gene CEACAM1, which caused their ileal samples to resemble the rectum.ConclusionsThese results imply that quantitative differences in splice usage contribute to the pathology of inflammatory bowel disease in a previously unrecognized manner.

Highlights

Aberrant splicing of individual genes is a well-known mechanism promoting pathology for a wide range of conditions, but disease is less commonly attributed to global disruption of exon usage
Location, and ancestry on splicing and gene expression In order to quantify the influences of disease, location, and ancestry on splicing and gene expression, we first computed the principal components (PC) for both the transcript abundance and PSI counts from the RNA-seq dataset and generated a weighted sum of the influences on these measures
40.3% of the variance was between locations, 2.3% between ancestry groups (European and African), 0.2% between disease subtypes (UC and Crohn’s disease (CD)), and 0.8% captured by the interaction between location and disease

Summary

Introduction

Aberrant splicing of individual genes is a well-known mechanism promoting pathology for a wide range of conditions, but disease is less commonly attributed to global disruption of exon usage. Global mis-regulation of the splicing of hundreds of genes due to aberrant activity of components of the spliceosome, is known to contribute to pathology for a variety of conditions, notably myelodysplastic syndrome, The inflammatory bowel diseases (IBD), ulcerative colitis (UC), and Crohn’s disease (CD) afflict approaching 1% of adults in developed countries and have been rising in prevalence globally for several decades [13]. To our knowledge, there have not been any reports of splicing defects in IBD, so we asked whether transcriptome profiles assessed

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