Full-length RNA isoforms in human colorectal cancer at single-cell resolution

Abstract

Dysregulated RNA splicing is a well-recognized characteristic of colorectal cancer. To investigate its intricacies, we used high-depth long-read single-cell RNA sequencing to profile normal and malignant epithelial cells from nine colorectal cancer patients at the individual isoform resolution. Rigorous analyses uncovered a systematically increased complexity in transcript diversity and splicing activity in cancer cells. Particularly, mRNAs in the stem/TA-like cancer cells exhibit significant 3'-UTR shortening accompanied with elevated expression levels of the corresponding genes. We also identified mutant allele-dominant expression patterns, notably in the oncogene KRAS, which impact cell migration and proliferation. Besides, specific splicing factors were upregulated in colorectal cancer cells, which were accompanied with reduced intron retention events. Furthermore, we revealed substantial shifts in isoform usage that result in alterations of protein sequences with distinct carcinogenic effects. Our work demonstrates intricate features of post-transcriptional regulation in colorectal cancer tumorigenesis, offering new insights for therapeutic interventions beyond gene-level analysis.

Biography

Dr. Lu obtained her PhD from Peking University in 2022 and is now a Post-doctoral Research Fellow in Bioinformatics, within Professor Fuchou Tang’s laboratory. Her research primarily explores transcriptomic and epigenetic regulation in development and cancer, utilizing self-developed single-cell functional genomics technologies based on both short-read and long-read sequencing platforms.