Spatial profiling of chromatin accessibility in mouse and human tissues
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Abstract
Cellular function in tissue is dependent on the local environment, requiring new methods for spatial mapping of biomolecules and cells in the tissue context 1 . The emergence of spatial transcriptomics has enabled genome-scale gene expression mapping 2–5 , but the ability to capture spatial epigenetic information of tissue at the cellular level and genome scale is lacking. Here we describe a method for spatially resolved chromatin accessibility profiling of tissue sections using next-generation sequencing (spatial-ATAC-seq) by combining in situ Tn5 transposition chemistry 6 and microfluidic deterministic barcoding 5 . Profiling mouse embryos using spatial-ATAC-seq delineated tissue-region-specific epigenetic landscapes and identified gene regulators involved in the development of the central nervous system. Mapping the accessible genome in the mouse and human brain revealed the intricate arealization of brain regions. Applying spatial-ATAC-seq to tonsil tissue resolved the spatially distinct organization of immune cell types and states in lymphoid follicles and extrafollicular zones. This technology progresses spatial biology by enabling spatially resolved chromatin accessibility profiling to improve our understanding of cell identity, cell state and cell fate decision in relation to epigenetic underpinnings in development and disease.
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The transposase-accessible chromatin sequencing (ATAC-Seq) assay is a powerful tool for investigating genome-wide chromatin accessibility.
“The transposase-accessible chromatin sequencing (ATAC-Seq) assay is also a powerful tool for investigating genome-wide chromatin accessibility.416,417”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [417]
DBiT-seq was the first reported spatial multi-omics technology to co-map tens of proteins and whole transcriptome.
“DBiT-seq was the first reported spatial multi-omics technology that demonstrated co-mapping of tens of proteins and with a whole transcriptome, and this method has further expanded to spatial epigenomics profiling of chromatin accessibility124 and histone modification125.”
From The technological landscape and applications of single-cell multi-omics (2023) · cites this paper as [124]
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Kim, Y., Cheng, W., Cho, C.-S., Hwang, Y., Si, Y., Park, A., Schrank, M., Hsu, J.-E., Anacleto, A., Xi, J., et al. (2025) · Nature Protocols · doi:10.1038/s41596-024-01065-0 · Cited by 44 · see citing works
- Authors
- Deng, Y., Bartosovic, M., Ma, S., Zhang, D., Kukanja, P., Xiao, Y., Su, G., Liu, Y., Qin, X., Rosoklija, G. B., Dwork, A. J., Mann, J. J., Xu, M. L., Halene, S., Craft, J. E., Leong, K. W., Boldrini, M., Castelo-Branco, G., & Fan, R.
- Affiliations
- Yale Cancer Center (US)
- Broad Institute (US)
- Yale University (US)
- Karolinska Institutet (SE)
- Columbia University (US)
- Macedonian Academy of Sciences and Arts (MK)
- New York State Psychiatric Institute (US)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Fan, Rong
- ORCID
- Venue
- Nature
- Published
- 2022-08-17
- Volume
- 609
- Issue
- 7926
- Pages
- 375-383
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC9452302
- OpenAlex
- W4292121951
- Cited by
- 417
- References
- 75
- Citations by year
- 2026: 105 · 2025: 106 · 2024: 84 · 2023: 91 · 2022: 25 · 2021: 5
- FWCI
- 24.97
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- ImmPort
- Funders
- Yale University
- Li Ka Shing Foundation
- Society for Immunotherapy of Cancer
- Göran Gustafssons Stiftelser
- European Commission (681893, HORIZON2020)
- Cancerfonden (190394 Pj, 2019-)
- Svenska Sällskapet för Medicinsk Forskning (JUB2019)
- Karolinska Institutet
- Knut och Alice Wallenbergs Stiftelse (2019–0107)
- Vetenskapsrådet (2019-01360)
- National Institutes of Health (UH3TR002151, 1rf1mh128876-01, UL1TR001863)
- Stand Up To Cancer
- National Institute on Aging (U54AG076043)
- National Institute of Mental Health (RF1 MH128876)
- National Cancer Institute (UH3CA257393, UG3CA257393, U54CA209992, R01CA245313, U01CA260507)
- National Institute of Diabetes and Digestive and Kidney Diseases (U54DK106857)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R37AR040072)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- spatial epigenomics, mouse embryo development, central nervous system development, brain regionalization, tonsil, lymphoid follicles
- MeSH terms
- Chromatin Immunoprecipitation Sequencing, Animals, Brain, Cell Differentiation, Chromatin, Humans, Palatine Tonsil, Genome, Cell Lineage, Gene Expression Profiling, Chromatin Assembly and Disassembly, Mice, Epigenomics, High-Throughput Nucleotide Sequencing
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