A widespread length-dependent splicing dysregulation in cancer

Abstract

Dysregulation of alternative splicing is a key molecular hallmark of cancer. However, the common features and underlying mechanisms remain unclear. Here, we report an intriguing length-dependent splicing regulation in cancers. By systematically analyzing the transcriptome of thousands of cancer patients, we found that short exons are more likely to be mis-spliced and preferentially excluded in cancers. Compared to other exons, cancer-associated short exons (CASEs) are more conserved and likely to encode in-frame low-complexity peptides, with functional enrichment in GTPase regulators and cell adhesion. We developed a CASE-based panel as reliable cancer stratification markers and strong predictors for survival, which is clinically useful because the detection of short exon splicing is practical. Mechanistically, mis-splicing of CASEs is regulated by elevated transcription and alteration of certain RNA binding proteins in cancers. Our findings uncover a common feature of cancer-specific splicing dysregulation with important clinical implications in cancer diagnosis and therapies.

The Batten disease gene product CLN5 is the lysosomal bis(monoacylglycero)phosphate synthase

“…Several studies reveal a deficiency of BMP in other mutated Batten disease genes (CLN3, CLN11) or alterations in BMPS lysosomal trafficking and/or abundance by loss of other Batten disease gene products (CLN6, CLN7, CLN8, CLN14) (9,10,25,47,(52)(53)(54). Given the identification of the Batten disease CLN5 gene product as the BMPS, BMP dyshomeostasis may be the unified metabolic defect in Batten disease.…”

m6A‐Modified circTET2 Interacting with HNRNPC Regulates Fatty Acid Oxidation to Promote the Proliferation of Chronic Lymphocytic Leukemia

“…Given the oncogenic role of circTET2 in CLL, targeting circTET2 was hypothesized to constitute a potential therapeutic strategy. Targeting splicing factors is regarded as a novel therapeutic strategy for tumors, [ 20 ] and since circTET2 was modulated by the splicing process and RBPs, we attempted to uncover splicing factor inhibitors that would target circTET2. We thereby applied five inhibitors: indisulam (targeting splicing by inducing RBM39 degradation); H3B‐8800 (a modulator of the SF3b complex); and the three pre‐mRNA splicing inhibitors isoginkgetin, madrasin, and CP028.…”

Delineating genotypes and phenotypes of individual cells from long-read single cell transcriptomes

“…Dysregulation of transcript isoforms plays critical roles in tumor progression 19, 25, 26, 27 . Long-read single cell sequencing technologies enable in-depth annotation of splicing isoforms at single cell levels.…”

“…In contrast, scNanoGPS achieves independent data deconvolution, corrects errors in gene bodies, and calculates same-cell mutations, isoforms, and gene expressions simultaneously for thousands of cells. 20,26,27,28 . Long-read single cell sequencing technologies enable in-depth annotation of splicing isoforms at single cell levels.…”