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Systematic characterization of single-cell full-length RNA isoforms in human colorectal cancer

ABSTRACT: Dysregulated RNA splicing is a well-recognized characteristic of colorectal cancer (CRC); however, its intricacies remain obscure, partly due to challenges in profiling full-length transcript variants at single-cell level. Here, we employ high-depth long-read scRNA-seq to define the full-length transcriptome of colorectal epithelial cells in 12 CRC patients, revealing extensive isoform diversities and splicing alterations. Cancer cells exhibited increased transcript complexity, with widespread 3'-UTR shortening and reduced intron retention. Distinct splicing regulation patterns were observed between intrinsic-consensus molecular subtypes (iCMS), with iCMS3 displaying even higher splicing factor activities and more pronounced 3'-UTR shortening. Furthermore, we revealed substantial shifts in isoform usage that result in alterations of protein sequences from the same gene with distinct carcinogenic effects during tumorigenesis of CRC. Allele-specific expression analysis revealed dominant mutant allele expression in key oncogenes and tumor suppressors. Moreover, mutated PPIG was linked to widespread splicing dysregulation, and functional validation experiments confirmed its critical role in modulating RNA splicing and tumor-associated processes. Our findings highlight the transcriptomic plasticity in CRC and suggest potentially novel targets for splicing-based therapeutic strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE248094 | GEO | 2025/07/29

REPOSITORIES: GEO

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Project description:The helicase-like transcription factor (HLTF) gene – a tumor suppressor in human colorectal cancer (CRC) - is regulated by alternative splicing and promoter hypermethylation. The detection of hypermethylated HLTF DNA in fecal occult blood tests is an indicator of disease recurrence and poor survival. Hltf-deficiency in the ApcMin/+ mouse strain increased the formation of intestinal adenocarcinoma with a high incidence of gross chromosomal instabilities. To investigate Hltf-deletion effects in CRC without cross-breeding into a tumorigenic strain, Hltf-deletion was studied in mice treated with the carcinogen azoxymethane (AOM) and the proinflammatory agent dextran sulfate (DSS). Hltf-deletion resulted in weight loss beginning at treatment week 6, and poor survival (Kaplan-Meier survival plot). Hltf-deletion increased tumor multiplicity compared to controls, and dramatically shifted the topographic distribution of lesions into the rectum. Differential isoform expression analysis of lesions from control mice revealed both the truncated isoform that lacks a DNA-repair domain and the full length isoform capable of DNA damage repair are present (3:1.8 ratio) during adenocarcinoma formation. iPathwayGuide identified 51 dynamically regulated genes of 10,967 total genes with measured expression. Oxidative Phosphorylation (Kegg: 00190), the top biological pathway (p=0.006; p value correction: Bonferroni) perturbed by Hltf-deletion, resulted from increased transcription of Atp5e, Cox7c, Uqcr11, Ndufa4 and Ndufb6 genes, concomitant with increased endogenous levels of ATP (p=0.0176). Upregulation of gene expression, as validated with qRT-PCR, was accompanied by a stable mtDNA/nDNA ratio. This is the first study to show Hltf-deletion in an inflammation-associated CRC model elevates mitochondrial bioenergetics. The distal shift in tumorigenesis indicates the detection of hypermethylated HLTF DNA in human stool samples might be a prognostic biomarker for distal (left-sided) colorectal cancer rather than proximal (right-sided) colon cancer.

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Systematic characterization of single-cell full-length RNA isoforms in human colorectal cancer

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