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Isoform-resolved transcriptome in patients with inflammatory bowel disease

ABSTRACT: Inflammatory bowel disease (IBD) is a group of chronic diseases that cause inflammation in the intestines, including ulcerative colitis (UC) and Crohn's disease (CD). Numerous omics studies have been published to understand IBD pathogenesis and identify potential targets for therapeutics. Despite the high amount RNA-seq data from short reads sequencing platforms produced to help preclinical and clinical research in IBD, such studies fail to capture the full-length mRNAs and various isoforms from alternative splicing events. Thus, the transcriptome associated with IBD has been understudied. The IsoSeq system of PacBio Sequel platforms enables sequence large number of long transcripts, and the corresponding IsoSeq pipeline and additional bioinformatics tools can identify the full-length transcripts and various isoforms. Here, we generate isoform-resolved transcriptome in IBD patients by performing long-read RNA sequencing on samples from four IBD patients and two healthy controls and integrate the full-length transcripts data with short-read RNA sequencing data from 99 IBD patients and controls. We identify numerous unannotated isoforms transcribed from both known and unannotated genes. Our bioinformatics pipeline further identified sQTL by integrating variants predicted from RNAseq with the isoforms from IsoSeq. We also identified isoform switch associated with IBD, and genes correlated with isoforms. Further pathway analysis and gene annotation search were conducted to understand the IBD disease. Together, our findings show that the transcriptome associated with IBD is far more complex than currently known, and our results will act as a valuable resource to empower future studies for IBD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE277415 | GEO | 2026/05/01

REPOSITORIES: GEO

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Project description:Dynamin-related protein 1 (Drp1, encoded by DNM1L) is a key regulator of mitochondrial fission, yet its functional role remains controversial, likely due to isoform-specific effects arising from alternative splicing. Conventional short-read RNA sequencing complicates the characterization of full-length isoforms, limiting our understanding of their biological significance. To resolve this, we applied a targeted long-read sequencing approach to capture full-length DNM1L transcripts in primary human left ventricle and iPSC-derived cardiomyocytes. We recovered the complete spectrum of annotated isoforms and found broadly conserved expression patterns, with isoforms 1-4 expressed most abundantly. Recombinant protein assays further revealed that isoform abundance does not directly predict enzymatic activity, emphasizing the need for combined expression and functional analyses. Extending this framework to mouse, we profiled Dnm1l isoforms across six tissues (brain, heart, skeletal muscle, lung, kidney, and spleen) using the same long-read pipeline. All annotated isoforms were recovered, with distinct tissue-enriched expression patterns. Notably, several isoforms displayed strong tissue specificity, with subsets preferentially expressed in brain, heart, or skeletal muscle, suggesting specialized regulatory roles in mitochondrial dynamics. Functional rescue experiments in Drp1-knockout mouse embryonic fibroblasts revealed isoform-dependent differences in mitochondrial fission activity. Isoforms lacking the A-insert within the GTPase domain (e.g., isoforms b and d) robustly restored mitochondrial fragmentation, whereas the canonical brain-enriched isoform (isoform e) and a muscle-enriched isoform (isoform o) exhibited only partial rescue. These results indicate that inclusion of exons 2 and 3 may negatively regulate Drp1 fission activity. Together, our work establishes a cross-species atlas of DNM1L/Dnm1l isoforms, integrating long-read transcriptomics with functional assays. We demonstrate that Drp1 isoform diversity is tightly linked to tissue identity and that structural differences among isoforms critically shape mitochondrial fission activity, offering new insights into the pathophysiology of Drp1 in human health and disease.

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Isoform-resolved transcriptome in patients with inflammatory bowel disease

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