Biology subjects

Coan, M.

Publications and source records attributed to Coan, M..

3 recordsLinked to original sources

bioRxiv2026

Organisational principles of long non-coding RNAs revealed by exon deletion

Long non-coding RNAs (lncRNAs) regulate cell phenotypes in health and disease, yet how function is encoded in their sequence remains poorly understood. Current models propose a modular architecture composed of discrete functional elements, but this is based on a limited set of paradigmatic examples and methods for mapping function to sequence are limited in scope and resolution. Here, we establish a high-throughput CRISPR-Cas9 strategy for dissecting lncRNA functional architecture at exon resolution. Using cell fitness as a phenotypic readout, we screened 358 exons from 107 lncRNAs across four human cell lines. We report that (1) a large proportion of exons have no detectable function, (2) a minority of exons are functional in any given cell line (19-111 exons), equivalent to one-fifth of total transcript nucleotides on average, and (3) functionality is enriched towards the 5 end of the transcript. We developed a database of putative lncRNA functional elements, ElementaLdb, and demonstrated through statistical and experimental analyses that lncRNA function depends on transposable elements, microRNA response elements and RNA binding protein sites. These sub-genic functional maps expand the catalogue of experimentally defined lncRNA functional elements by an order of magnitude, illuminate molecular mechanisms and broadly support a modular organisation for lncRNAs.

genomics↗

bioRxiv2026

Pan-cancer discovery of driver mutations in long noncoding RNAs reveals widespread functional rewiring of RNA regulatory elements

Most somatic mutations in cancer occur outside protein-coding genes, yet the functional impact of these mutations remains largely unknown. Long noncoding RNAs (lncRNAs) represent a major class of cancer-promoting genes whose molecular mechanisms are poorly understood. While individual driver mutations in lncRNAs have been identified, detecting such driver lncRNAs at scale requires large tumour genome cohorts. We analyse 12,631 cancer genomes from the 100,000 Genomes Project (100kGP) and identify 121 lncRNAs under positive selection across 19 cancer types. These driver lncRNAs are independently supported by functional genomic screens, germline predisposing variants, mutual exclusivity with protein-coding drivers, and independent oncogenic lncRNA catalogues. Overall, approximately two-thirds of analysed tumours harbour at least one lncRNA driver mutation. Leveraging the depth of this dataset, we demonstrate that somatic mutations preferentially target and remodel RNA-binding protein (RBP) interaction sites to potentiate oncogenic lncRNAs, including MALAT1, SNHG14 and NEAT1. From these data, we derive a model in which somatic mutations liberate oncogenic lncRNAs from repressive RNA:protein interactions. This work expands the number and nature of cancer driver genes, identifies targets for RNA-directed therapies, and demonstrates that with large tumour mutation catalogues we can dissect the molecular mechanisms of noncoding genes.

Cancer Biology↗

bioRxiv2025

Robust CRISPR Screens Identify TPL1 as a Novel Long Noncoding RNA Driving Triple-Negative Breast Cancer Hallmarks

Despite the growing catalog of long noncoding RNAs (lncRNAs), the functional roles of their vast majority in cancer remain poorly defined. To systematically explore lncRNA dependencies in triple-negative breast cancer (TNBC), we compiled a comprehensive annotation by merging GENCODE, BIGTranscriptome, and MiTranscriptome databases and performed a CRISPR-Cas9 deletion screen targeting 1,029 TNBC-enriched lncRNAs. The screen revealed several essential lncRNAs and those modulating doxorubicin sensitivity, with TPL1 emerging among top hits. TPL1 silencing significantly impaired TNBC cell proliferation in both 2D and 3D cultures and reduced invasive capacity in an organ-on-chip model. Transcriptomic and proteomic profiling following TPL1 knockdown revealed downregulation of genes involved in ECM-receptor interaction, focal adhesion, cell migration, and PI3K-Akt signaling. Mechanistically, TPL1 directly interacted with key proteins including EIF4B, MDM2, TARBP2, TLE5, and GTPase RAN, suggesting TPL1 could regulate RNA processing, transcriptional repression, and translation, as well as modulate GTPase signaling pathways. Additionally, TPL1 functioned as a competing endogenous RNA (ceRNA), sequestering miR-10396b-5p, miR-486-3p, and miR-450a-2-3p, among others, thereby modulating expression of pro-tumorigenic targets. Clinically, TPL1 was significantly overexpressed in TNBC tissues, particularly in the BLIS subtype. Collectively, our findings highlight TPL1 as a key regulator of TNBC molecular networks and a promising therapeutic target.

cancer biology↗