Imaging-based spatial isoform transcriptomics resolves transcript diversity at cellular and subcellular resolution

McAndrew, E.; Fierville, M.; Gautier-Isola, M.; Pignol, M.; Arguel, M.-J.; Cadis, H.; Barres, R.; Mari, B.; BARBRY, P.; Lebrigand, K.

doi:10.64898/2026.09.22.753429

bioRxiv · 10.64898/2026.09.22.753429

Imaging-based spatial isoform transcriptomics resolves transcript diversity at cellular and subcellular resolution

McAndrew, E.·Fierville, M.·Gautier-Isola, M.·Pignol, M.·Arguel, M.-J.·Cadis, H.·Barres, R.·Mari, B.·BARBRY, P.·Lebrigand, K.

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Abstract

Spatial transcriptomics has transformed our understanding of tissue organization, yet current high-throughput approaches remain largely confined to a gene-centric paradigm, precluding systematic characterization of spatially resolved transcript isoform diversity. Here, we introduce imaging-based spatial isoform transcriptomics (iSiT), a framework enabling simultaneous large-scale gene expression and targeted transcript isoform profiling on the commercial Xenium platform. iSiT resolves alternative splicing events that alter internal transcript structure at cellular and subcellular resolution using a single junction-specific probe per target. To facilitate broader adoption, we developed ProbeHarbour, an open-source toolkit for the design, characterization and management of isoform-specific probes. We demonstrate iSiT in the postnatal mouse brain by combining the Prime 5K gene-level panel with isoform-specific detection of 45 synaptogenesis-associated genes. By extending spatial transcriptomics beyond gene-level measurements, iSiT provides a scalable and readily accessible framework for investigating spatial isoform regulation in development and disease.

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McAndrew, E., Fierville, M., Gautier-Isola, M., Pignol, M., Arguel, M.-J., Cadis, H., Barres, R., Mari, B., BARBRY, P., Lebrigand, K.. 2026-09-28. Imaging-based spatial isoform transcriptomics resolves transcript diversity at cellular and subcellular resolution. https://doi.org/10.64898/2026.09.22.753429

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