Slide-tags enables single-nucleus barcoding for multimodal spatial genomics

Andrew J. C. Russell, Jackson A. Weir, Naeem M. Nadaf, Matthew Shabet, Vipin Kumar, Sandeep Kambhampati, Ruth Raichur, Giovanni J. Marrero, Sophia Liu, Karol S. Balderrama, Charles R. Vanderburg, Vignesh Shanmugam, Luyi Tian, J. Bryan Iorgulescu, Charles H. Yoon, Catherine J. Wu, Evan Z. Macosko () and Fei Chen ()
Additional contact information
Andrew J. C. Russell: Broad Institute of Harvard and MIT
Jackson A. Weir: Broad Institute of Harvard and MIT
Naeem M. Nadaf: Broad Institute of Harvard and MIT
Matthew Shabet: Broad Institute of Harvard and MIT
Vipin Kumar: Broad Institute of Harvard and MIT
Sandeep Kambhampati: Broad Institute of Harvard and MIT
Ruth Raichur: Broad Institute of Harvard and MIT
Giovanni J. Marrero: Broad Institute of Harvard and MIT
Sophia Liu: Broad Institute of Harvard and MIT
Karol S. Balderrama: Broad Institute of Harvard and MIT
Charles R. Vanderburg: Broad Institute of Harvard and MIT
Vignesh Shanmugam: Broad Institute of Harvard and MIT
Luyi Tian: Broad Institute of Harvard and MIT
J. Bryan Iorgulescu: Broad Institute of Harvard and MIT
Charles H. Yoon: Brigham and Women’s Hospital, Harvard Medical School
Catherine J. Wu: Broad Institute of Harvard and MIT
Evan Z. Macosko: Broad Institute of Harvard and MIT
Fei Chen: Broad Institute of Harvard and MIT

Nature, 2024, vol. 625, issue 7993, 101-109

Abstract: Abstract Recent technological innovations have enabled the high-throughput quantification of gene expression and epigenetic regulation within individual cells, transforming our understanding of how complex tissues are constructed1–6. However, missing from these measurements is the ability to routinely and easily spatially localize these profiled cells. We developed a strategy, Slide-tags, in which single nuclei within an intact tissue section are tagged with spatial barcode oligonucleotides derived from DNA-barcoded beads with known positions. These tagged nuclei can then be used as an input into a wide variety of single-nucleus profiling assays. Application of Slide-tags to the mouse hippocampus positioned nuclei at less than 10 μm spatial resolution and delivered whole-transcriptome data that are indistinguishable in quality from ordinary single-nucleus RNA-sequencing data. To demonstrate that Slide-tags can be applied to a wide variety of human tissues, we performed the assay on brain, tonsil and melanoma. We revealed cell-type-specific spatially varying gene expression across cortical layers and spatially contextualized receptor–ligand interactions driving B cell maturation in lymphoid tissue. A major benefit of Slide-tags is that it is easily adaptable to almost any single-cell measurement technology. As a proof of principle, we performed multiomic measurements of open chromatin, RNA and T cell receptor (TCR) sequences in the same cells from metastatic melanoma, identifying transcription factor motifs driving cancer cell state transitions in spatially distinct microenvironments. Slide-tags offers a universal platform for importing the compendium of established single-cell measurements into the spatial genomics repertoire.

Date: 2024
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DOI: 10.1038/s41586-023-06837-4

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