Zhou S et al., Cancer-associated snaR-A noncoding RNA interacts with core splicing machinery and disrupts processing of mRNA subpopulations. Nature Communications - snaR-A noncoding RNA interacts with U2 snRNP subunit SF3B2 and nuclear speckles, increasing intron retention and promoting proliferation in human cancer-relevant cells.

Study Highlights:
Using human cell lines (HEK293T, A549, THP-1) and tumor chromatin data, the authors combined biotinylated RNA pulldown mass spectrometry, PAR-CLIP/CLIP-qPCR, HCR-RNA-FISH, TSA-seq, and ultra-deep RNA-seq (IRFinder, rMATS) to map snaR-A interactions and splicing outcomes. snaR-A directly binds splicing factors and shows nucleotide-level crosslinking to the U2 snRNP protein SF3B2, and localizes to subnuclear foci adjacent to nuclear speckles and U6-containing sites. Functionally, snaR-A overexpression increases intron retention and selectively depletes SF3B2 protein, whereas snaR-A depletion reduces intron retention for transcripts with high U2 occupancy and speckle proximity. These splicing changes alter protein abundance for multiple targets and coincide with reduced proliferation after snaR-A depletion, consistent with tumor-level associations to growth.

Conclusion:
snaR-A acts as a molecular antagonist of U2-dependent splicing by interacting with SF3B2 and perturbing processing of specific mRNA subpopulations, promoting intron retention and proliferation in cancer-relevant contexts.

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Reference:
Zhou S., Lizarazo S., Chorghade S., Mouli L., Cheng R., Rajendra K. C., Kalsotra A., Van Bortle K. Cancer-associated snaR-A noncoding RNA interacts with core splicing machinery and disrupts processing of mRNA subpopulations. Nature Communications. 2025;16:10460. https://doi.org/10.1038/s41467-025-65448-x

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/

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On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/snar-a-sf3b2-splicing

Yu M et al., Cell Genomics. 6 ( - Large-scale exome sequencing shows CFTR risk variants, including deltaF508, reduce susceptibility to inflammatory bowel disease, suggesting targeted CFTR modulation as a potential IBD therapy.

Study Highlights:
The authors analyzed large-scale human exome and genome sequencing data (38,558 cases and 66,945 controls in European discovery; 42,475 cases and 192,050 controls in replication across ancestries) using single-variant tests and gene-based rare-variant burden tests. They report a protective single-variant association for CFTR deltaF508 with IBD (meta-analysis p = 8.96E-11, OR = 0.82) and a significant protective gene-level burden of clinically annotated CF-risk variants (meta-analysis p = 3.9E-7, OR = 0.85). The study also compared variant prioritization methods and found clinically curated CFTR2 annotations outperform in silico predictors such as AlphaMissense for powering burden tests. Replication signals were observed in non-European groups at nominal significance and the results support exploration of selective, tissue-targeted CFTR modulators as a potential therapeutic implication.

Conclusion:
Clinically annotated CFTR risk variants, including deltaF508, confer a reproducible protective effect against IBD in large sequencing cohorts, supporting investigation of selective tissue-targeted CFTR modulation while balancing cystic fibrosis risks.

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Reference:
Yu M., Zhang Q., Yuan K., Sazonovs A., Stevens C.R., Fachal L., et al. Cystic fibrosis risk variants confer protection against inflammatory bowel disease. Cell Genomics. 6 (2026) 101071. https://doi.org/10.1016/j.xgen.2025.101071

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/

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On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

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Hunter CE et al., The EMBO Journal - Review shows how alternative splicing, via TE exonization and cis-regulatory changes and revealed by long-read RNA-seq, reshapes gene regulation and drives phenotypic evolution in mammals.

Study Highlights:
This review synthesizes comparative transcriptomic studies across multicellular eukaryotes with emphasis on vertebrates and mammals. It highlights methods including short- and long-read RNA-seq, single-cell transcriptomics, and MS proteomics to map isoform diversity. The authors emphasize that lineage-specific AS is often driven by cis-regulatory changes and exonization of transposable elements, with trans-factor innovations (e.g., SRRM3/4, PTBP1 isoforms) modulating microexons and isoform ratios. Functional examples linking AS to phenotypes include an Alu-derived IFNAR2 decoy receptor reducing JAK/STAT signaling, TNNI3 exon3 loss or skipping associated with extreme heart rates, and hominoid shifts in MAPT exon10 splicing altering tau isoform proportion.

Conclusion:
Alternative splicing, shaped largely by cis-sequence changes and TE exonization and illuminated by long-read and single-cell transcriptomics, is a flexible evolutionary mechanism that can produce lineage-specific regulatory and phenotypic innovations.

Music:
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Reference:
Hunter CE, Xing Y. The splice of life: how alternative splicing shapes regulatory and phenotypic evolution. The EMBO Journal. 2026. https://doi.org/10.1038/s44318-025-00666-z

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/

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On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/alternative-splicing-exonization-evolution