Category Ranking
98%
Total Visits
921
Avg Visit Duration
2 minutes
Citations
20
Article Abstract
Exon skipping (ES) is the most prevalent form of alternative splicing and a hallmark of tumorigenesis, yet its functional roles remain underexplored. Here, we present a CRISPR-RfxCas13d-based platform for transcript-specific silencing of ES-derived isoforms using guide RNAs (gRNAs) targeting exon-exon junctions. We designed a transcriptome-wide gRNA library against 3,744 human ES events and conducted loss-of-function screens in colorectal cancer (CRC) cells in vitro and in vivo. This screen uncovered multiple ES events essential for CRC growth, notably HMGN3 Δ6, an isoform arising from exon 6 skipping, which enhanced tumor proliferation. Functional validation confirmed the oncogenic role of HMGN3 Δ6 and its necessity for CRC progression. Our study establishes CRISPR-RfxCas13d as a powerful tool for isoform-specific functional genomics and reveals a widespread, previously uncharacterized layer of tumor biology driven by ES. These findings position ES-derived transcripts as promising targets for therapeutic intervention in cancer.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.cels.2025.101351 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Dual Targets, Two Paths: Amivantamab: A Promising Treatment for NSCLC With Exon 14 Skipping Mutations of MET.
J Thorac Oncol
September 2025
Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan. Electronic address:
A single-cell, long-read, isoform-resolved case-control study of FTD reveals cell-type-specific and broad splicing dysregulation in human brain.
Cell Rep
September 2025
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA; Center for Neurogenetics, Weill Cornell Medicine, New York, NY, USA. Electronic address:
Progranulin-deficient frontotemporal dementia (GRN-FTD) is a major cause of familial FTD with TAR DNA-binding protein 43 (TDP-43) pathology, which is linked to exon dysregulation. However, little is known about this dysregulation in glial and neuronal cells. Here, using splice-junction-covering enrichment probes, we introduce single-nuclei long-read RNA sequencing 2 (SnISOr-Seq2), targeting 3,630 high-interest genes without loss of precision, and complete the first single-cell, long-read-resolved case-control study for neurodegeneration.
View Article and Find Full Text PDFvariants drive chromosomal fission and accelerate speciation in zokors.
Sci Adv
September 2025
State Key Laboratory of Herbage Improvement and Grassland Agro-Ecosystems, College of Ecology, Lanzhou University, Lanzhou, P. R. China.
Chromosomal fissions and fusions are common, yet the molecular mechanisms and implications in speciation remain poorly understood. Here, we confirm a fission event in one zokor species through multiple-omics and functional analyses. We traced this event to a mutation in a splicing enhancer of the DNA repair gene in the fission-bearing species, which caused exon skipping and produced a truncated protein that disrupted DNA repair.
View Article and Find Full Text PDFTargeting a pathogenic cryptic exon that drives HLRCC to induce exon skipping.
Mol Ther Nucleic Acids
September 2025
Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant cancer predisposition syndrome driven by the loss of fumarate hydratase (FH) activity. Recently, we identified a pathogenic variant in intron 9 of the gene that disrupts splicing by creating a novel splice acceptor site, resulting in the aberrant inclusion of a cryptic exon. Inclusion of the cryptic exon introduces a premature termination codon, leading to loss of FH activity.
View Article and Find Full Text PDFA combinatorial oligonucleotide therapy to improve dystrophin restoration and dystrophin-deficient muscle health.
Mol Ther Nucleic Acids
September 2025
Center for Genetic Medicine Research, Children's National Research Institute, Children's National Research and Innovation Campus, Children's National Hospital, Washington, DC 20012, USA.
Despite the proven safety of dystrophin-targeting phosphorodiamidate morpholino oligomer (PMO) therapy, poor delivery of the PMOs limit the efficacy of this dystrophin restoring gene therapy for Duchenne muscular dystrophy (DMD). Limited myogenesis and excessive fibrosis in DMD are pathological features that contribute to the poor efficacy of PMOs. We show that the severe DMD mouse model (D2-) not only replicates these pathological features of DMD but also mirrors the resulting PMO-mediated dystrophin restoration deficit.
View Article and Find Full Text PDF