This video introduces Slide-tags, a novel technology designed to bridge high-resolution single-cell genomics with spatial tissue measurements. Addressing the challenge of dissociated single-cell data lacking spatial context, Slide-tags employs 10-micron barcoded beads arrayed on a glass slide. A tissue section is then melted onto the array, and UV light cleaves barcoded oligonucleotides that diffuse into individual nuclei. These spatially barcoded nuclei are then compatible with existing single-nucleus sequencing platforms, adding only about 10 minutes to the workflow. The technology delivers true single-cell data with high spatial resolution (approximately 3.5 microns), maintaining quality indistinguishable from standard methods and integrating seamlessly with current analysis tools. Validated in mouse hippocampus and applied to various human tissues (cortex, tonsil, metastatic melanoma), Slide-tags effectively maps genomic and epigenomic profiles back to their precise tissue locations, revealing spatial organization of cell types, gene expression, distinct tumor clones, and their associated immune microenvironments. The platform is designed for broad applicability, with efforts towards future commercialization to democratize spatial genomics.
Exploring Slide-tags: Unifying Single-Cell Genomics with Spatial Context
0:09 Bridging Genomics and Tissue Measurements: The research aims to connect high-resolution genomic data from single cells with spatial information from tissue measurements, addressing the common issue where genomic analyses lack cellular location context.
1:24 The Slide-tags Innovation: Slide-tags is presented as a method to unify single-cell sequencing with precise spatial localization, allowing researchers to know the exact origin of cells being sequenced.
1:40 How Slide-tags Works: The process involves 10-micron beads, each coated with millions of oligonucleotides containing a unique spatial barcode. These beads are arrayed on a glass slide, and their spatial XY location is determined by in-situ sequencing. A tissue section is then placed on the array, and UV light cleaves the oligos, which diffuse into individual nuclei, barcoding them based on their location. These barcoded nuclei are then used as input for established single-nucleus sequencing platforms.
2:21 Key Advantages: Slide-tags provides true single-cell data with spatial resolution, offering data quality indistinguishable from standard single-nucleus RNA sequencing (snRNA-seq). It is compatible with any existing snRNA-seq platforms, multi-omic technologies, and current single-cell analysis tools.
3:05 Minimal Workflow Impact: The entire tagging procedure adds only approximately 10 minutes to the upstream workflow time for single-nucleus preparation.
3:45 High Spatial Resolution: The technique allows for highly accurate localization of nuclei, achieving an approximate resolution of 3.5 microns, which is comparable to the size of a nuclear radius.
4:15 Validation in Mouse Hippocampus: The technology was validated using the mouse hippocampus, demonstrating its ability to accurately localize cells and gene expressions, mapping them between abstract dimensionality reduction plots and real tissue space.
5:10 Diverse Human Tissue Applications: Slide-tags has been applied to various human tissues, including the cortex (defining cell subtypes and spatially varying genes), tonsil (predicting receptor-ligand interactions important for immune responses), and metastatic melanoma.
5:40 Multimodal Capability in Melanoma: In a human metastatic melanoma sample, Slide-tags showcased its multimodal capacity by enabling simultaneous single-nucleus RNA-seq, single-cell ATAC-seq (chromatin accessibility), and TCR enrichment (T-cell clonality) on the same spatially barcoded cells.
6:25 Uncovering Tumor Heterogeneity: This multimodal approach revealed that transcriptionally and epigenetically distinct tumor clusters also spatially divide within the tissue. Furthermore, inferred copy number variations suggested these were genomically distinct tumor clones, with differences in their microenvironments and the infiltration of cytotoxic T-cell clonotypes.
7:55 Accessibility and Future Outlook: Detailed protocols and data for Slide-tags are publicly available on GitHub. The workflow is designed for simplicity to maximize adoption. The lab is actively producing and fulfilling requests for barcoded arrays, is open to collaborations, and anticipates future commercialization to democratize the technology's access.