Cited by 422Single-cell and spatial transcriptomicsGenomics and Phylogenetic StudiesRNA Research and Splicing

RNA-sequencing from single nuclei

Open access
Grindberg, Rashel V., Yee-Greenbaum, Joyclyn L., McConnell, Michael J., Novotny, Mark, O’Shaughnessy, Andy L., Lambert, Georgina M., Araúzo-Bravo, Marcos J., Lee, Jun +8 more·2013·Proceedings of the National Academy of Sciences

Abstract

Significance: One of the central goals of developmental biology and medicine is to ascertain the relationships between the genotype and phenotype of cells. Single-cell transcriptome analysis represents a powerful strategy to reach this goal. We advance these strategies to single nuclei from neural progenitor cells and dentate gyrus tissue, from which it is very difficult to recover intact cells. This provides a unique means to carry out RNA sequencing from individual neurons that avoids requiring isolation of single-cell suspensions, eliminating potential changes in gene expression due to enzymatic-cell dissociation methods. This method will be useful for analysis of processes occurring in the nucleus and for gene-expression studies of highly interconnected cells such as neurons.

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Crossref · 10.1073/pnas.1319700110

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  • The central nervous system of older mice is more complex than that of younger mice, making it harder to dissociate it into single cells, and as a result some cell types can get over- or underrepresented.

    “The central nervous system of older mice is more complex than that of younger mice, making it harder to dissociate it into single cells, and as a result some cell types can get over-or underrepresented (Darmanis et al., 2015;Grindberg et al., 2013;Krishnaswami et al., 2016;Lake et al., 2016;Lake et al., 2017;Tasic et al., 2018).”

    From Single-cell resolution analysis of the crosstalk between chemogenically activated astrocytes and microglia (2020) · cites this paper as Grindberg et al., 2013

    The Discussion (page unavailable) says that intact single cells are difficult to isolate from complex CNS tissue, supporting the dissociation difficulty. It does not compare older and younger mice or say that dissociation over- or underrepresents particular cell types. (LLM, conf=0.88)

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  • snRNA-seq generates transcriptional profiles with high similarity to scRNA-seq while offering advantages: nuclei are promptly released during homogenization, minimizing cell type biases and artifactual transcriptional alteration; it is compatible with cryopreserved samples; and it can study cell types less amenable to scRNA-seq such as adipocytes and cardiomyocytes.

    “While generating transcriptional profiles with high similarity to those by scRNA-seq (Grindberg et al., 2013; Habib et al., 2017), snRNA-seq offers advantages. First, this method utilizes nuclei that are promptly released from tissues during homogenization, obviating the need for an extended digestion process and thereby minimizing cell type biases and artifactual transcriptional alteration.”

    From Robust single-nucleus RNA sequencing reveals depot-specific cell population dynamics in adipose tissue remodeling during obesity (2025) · cites this paper as Grindberg et al., 2013

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  • Single-nucleus RNA-seq was developed to analyze RNA in nuclei from fresh, frozen, or lightly fixed tissues.

    “To address this challenge, we3 and others4–6 developed single nucleus RNA-seq (snRNA-seq) for analysis of RNA in single nuclei from fresh, frozen or lightly fixed tissues.”

    From Massively parallel single-nucleus RNA-seq with DroNc-seq (2017) · cites this paper as [6]

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Authors
Grindberg, R. V., Yee-Greenbaum, J. L., McConnell, M. J., Novotny, M., O’Shaughnessy, A. L., Lambert, G. M., Araúzo-Bravo, M. J., Lee, J., Fishman, M., Robbins, G. E., Lin, X., Venepally, P., Badger, J. H., Galbraith, D. W., Gage, F. H., & Lasken, R. S.
Affiliations
  • J. Craig Venter Institute (US)
  • University of Virginia (US)
  • J. Craig Venter Institute, San Diego, CA 92121;
  • University of Arizona (US)
  • Max Planck Institute for Molecular Biomedicine (DE)
  • LeGene Biosciences, San Diego, CA 92126;
  • Applied Biosystems, Life Technologies, Foster City, CA 94404;
  • Salk Institute for Biological Studies (US)
Venue
Proceedings of the National Academy of Sciences
Published
2013-11-18
Volume
110
Issue
49
Pages
19802-19807
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2112630596
Cited by
422
References
55
Citations by year
2026: 23 · 2025: 29 · 2024: 39 · 2023: 67 · 2022: 56 · 2021: 44 · 2020: 44 · 2019: 34 · 2018: 23 · 2017: 18 · 2016: 14 · 2015: 6 · 2014: 21 · 2013: 3 · 2012: 1
FWCI
6.56
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • James S. McDonnell Foundation
  • JPB Foundation
  • G. Harold and Leila Y. Mathers Foundation
  • National Institutes of Health
  • College of Agriculture and Life Sciences, University of Arizona
  • National Institute of Mental Health (TRO1MH095741, R01MH095741)
  • National Human Genome Research Institute (NIH-1 RC1 HG005471, NIH 2R01 HG003647, R01HG003647, RC1HG005471)
  • National Cancer Institute (NIH-NCI R21-CA164690, R21CA164690)
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 Phylogenetic Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
Keywords
single-nucleus RNA sequencing, single-nucleus transcriptomics, single-cell transcriptomics, gene expression quantification, hippocampus
MeSH terms
Animals, Cell Nucleus, Flow Cytometry, Micromanipulation, Microscopy, Fluorescence, Dentate Gyrus, Gene Expression Profiling, Mice, Embryonic Stem Cells, Neural Stem Cells, High-Throughput Nucleotide Sequencing

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