Spatially tunable multiomic sequencing using light-driven combinatorial barcoding of molecules in tissues.

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dc.creatorBattistoni, Giorgia
dc.creatorTorres-Garcia, Sito
dc.creatorSia, Chee Ying
dc.creatorCorriero, Silvia
dc.creatorBoquetale, Carla
dc.creatorWilliams, Elena
dc.creatorCregeen, Anna
dc.creatorWasilewska, Karolina
dc.creatorAlini, Martina
dc.creatorHemmer, Nicole
dc.creatorIMAXT Cancer Grand Challenge Consortium
dc.creatorBalasubramanian, Shankar
dc.creatorNicholson, Benjamin Czech
dc.creatorHannon, Gregory J
dc.creatorBressan, Dario
dc.date2026-05-18T19:23:04Z
dc.date2026-05-26
dc.date2025-10-01
dc.date2026-05-18T19:23:03Z
dc.date.accessioned2026-08-03T02:33:52Z
dc.descriptionPeer reviewed: True
dc.descriptionPublication status: Published
dc.descriptionMapping the molecular identities and functions of cells within their spatial context is key to understanding the complex interplay within and between tissue neighborhoods. A wide range of methods have recently enabled spatial profiling of cellular anatomical contexts, some offering single-cell resolution. These use different barcoding schemes to encode either the location or the identity of target molecules. However, all these technologies face a trade-off between spatial resolution, depth of profiling, and scalability. Here, we present Barcoding by Activated Linkage of Indexes (BALI), a method that uses light to write combinatorial spatial molecular barcodes directly onto target molecules in situ, enabling multiomic profiling by next generation sequencing. A unique feature of BALI is that the user can define the number, size, shape, and resolution of the spatial locations to be interrogated, with the potential to profile millions of distinct regions with subcellular precision. As a proof of concept, we used BALI to capture the transcriptome, chromatin accessibility, or both simultaneously, from distinct areas of the mouse brain in single tissue sections, demonstrating strong concordance with publicly available datasets. We also developed an integrated instrument that automates combinatorial barcode writing on tissue sections, enabling high-throughput profiling. BALI therefore combines high spatial resolution, high throughput, compatibility with standard histological pipelines, and workflow accessibility to enable tunable spatial multi-omic profiling.
dc.descriptionThis work was supported by the IMAXT Cancer Grand Challenge grant (A24042 to GJH and DB), CRUK Pioneer Award (G104344 to DB), Wellcome Trust Investigator Award (110161/Z/15/Z to GJH), a Cancer Research UK core award (A21143 to GJH) and Herchel Smith funds (to SB). GJH is a Royal Society Wolfson Research Professor (RSRP\R\200001) and Wellcome Trust Investigator. SB is a Herchel Smith Professor (University of Cambridge) and Wellcome Trust Senior Investigator (209441/Z/17.Z). ST-G was partially supported by The Branco Weiss Fellowship - Society in Science, administered by ETH Zürich. The authors’ work at the University of Cambridge is supported by the NIHR Cambridge Biomedical Research Center (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care
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dc.identifier0027-8424
dc.identifier202527896
dc.identifierhttps://www.repository.cam.ac.uk/handle/1810/403267
dc.identifier1091-6490
dc.identifier.urihttps://repo.dare.co.zw/handle/123456789/167542
dc.languageen
dc.languageeng
dc.publisherProceedings of the National Academy of Sciences
dc.publisherhttps://doi.org/10.1073/pnas.2527896123
dc.subjectRNA expression
dc.subjectchromatin accessibility
dc.subjectspatial profiling
dc.subjectAnimals
dc.subjectMultiomics
dc.subjectMice
dc.subjectHigh-Throughput Nucleotide Sequencing
dc.subjectTranscriptome
dc.subjectSpatial Transcriptomics
dc.subjectBrain
dc.subjectChromatin
dc.subjectGene Expression Profiling
dc.titleSpatially tunable multiomic sequencing using light-driven combinatorial barcoding of molecules in tissues.
dc.typeArticle

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