High-throughput sequencing of the transcriptome and chromatin accessibility in the same cell
Open accessAbstract
Single-cell RNA sequencing can reveal the transcriptional state of cells, yet provides little insight into the upstream regulatory landscape associated with open or accessible chromatin regions. Joint profiling of accessible chromatin and RNA within the same cells would permit direct matching of transcriptional regulation to its outputs. Here, we describe droplet-based single-nucleus chromatin accessibility and mRNA expression sequencing (SNARE-seq), a method that can link a cell's transcriptome with its accessible chromatin for sequencing at scale. Specifically, accessible sites are captured by Tn5 transposase in permeabilized nuclei to permit, within many droplets in parallel, DNA barcode tagging together with the mRNA molecules from the same cells. To demonstrate the utility of SNARE-seq, we generated joint profiles of 5,081 and 10,309 cells from neonatal and adult mouse cerebral cortices, respectively. We reconstructed the transcriptome and epigenetic landscapes of major and rare cell types, uncovered lineage-specific accessible sites, especially for low-abundance cells, and connected the dynamics of promoter accessibility with transcription level during neurogenesis.
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Milo may also be useful for single-cell assays beyond scRNA-seq, including multi-omic assays.
“Milo may also be applicable to single-cell assays other than scRNA-seq, including multi-omic assays [35–39].”
From Differential abundance testing on single-cell data using k-nearest neighbor graphs (2022) · cites this paper as [37]
SNARE-seq applied droplet microfluidics to measure more than 10,000 mRNA transcripts and chromatin accessibility in the same cell.
“As an alternative, single-nucleus chromatin accessibility and mRNA expression sequencing (SNARE-seq) used droplet-based microfluidics to co-profile over 10,000 mRNA transcripts with chromatin accessibility from the same single cell57.”
From The technological landscape and applications of single-cell multi-omics (2023) · cites this paper as [57]
Paired experimental methods are easier computationally because modalities can be tethered to a single cell or spot, but sequencing capacity of each modality decreases overall sample size.
“By contrast, paired experimental methods (10x Multiome, SHARE-seq60, DBiT-seq123, SNARE-seq57, CITE-seq68 and others) are easier to work with computationally as different modalities can be tethered to a single cell or a single spot; however, the sequencing capacity of each modality causes the overall sample size to decrease.”
From The technological landscape and applications of single-cell multi-omics (2023) · cites this paper as [57]
Single-cell multiomics allows uncovering mechanisms of gene regulation across different omics layers but lacks spatial information, which is crucial to understanding cellular function in tissue.
“Single-cell multiomics allows uncovering of the mechanisms of gene regulation across different omics layers6–9 but lacks spatial information, which is crucial to understanding cellular function in tissue.”
From Spatial epigenome–transcriptome co-profiling of mammalian tissues (2023) · cites this paper as [7]
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- Authors
- Chen, S., Lake, B. B., & Zhang, K.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Zhang, Kun
- Venue
- Nature Biotechnology
- Published
- 2019-10-14
- Volume
- 37
- Issue
- 12
- Pages
- 1452-1457
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC6893138
- OpenAlex
- W2979911343
- Cited by
- 810
- References
- 19
- Citations by year
- 2026: 95 · 2025: 117 · 2024: 130 · 2023: 145 · 2022: 133 · 2021: 125 · 2020: 58 · 2019: 7
- FWCI
- 26.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (U01MH098977)
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (R01HL123755, U54HL145608)
- 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
- single-cell transcriptomics, Tn5 transposase, promoter accessibility, neurogenesis, cerebral cortex, rare cell types, epigenetic regulation
- MeSH terms
- Animals, Cells, Cultured, Cerebral Cortex, Chromatin, RNA, Messenger, Sequence Analysis, RNA, Computational Biology, Mice, High-Throughput Nucleotide Sequencing, Transcriptome
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