Cited by 228Single-cell and spatial transcriptomicsGene Regulatory Network AnalysisGenomics and Chromatin Dynamics

SEACells infers transcriptional and epigenomic cellular states from single-cell genomics data

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Persad, Sitara, Choo, Zi-Ning, Dien, Christine, Sohail, Noor, Masilionis, Ignas, Chaligné, Ronan, Nawy, Tal, Brown, Chrysothemis C. +4 more·2023·Nature Biotechnology

Abstract

Metacells are cell groupings derived from single-cell sequencing data that represent highly granular, distinct cell states. Here we present single-cell aggregation of cell states (SEACells), an algorithm for identifying metacells that overcome the sparsity of single-cell data while retaining heterogeneity obscured by traditional cell clustering. SEACells outperforms existing algorithms in identifying comprehensive, compact and well-separated metacells in both RNA and assay for transposase-accessible chromatin (ATAC) modalities across datasets with discrete cell types and continuous trajectories. We demonstrate the use of SEACells to improve gene–peak associations, compute ATAC gene scores and infer the activities of critical regulators during differentiation. Metacell-level analysis scales to large datasets and is particularly well suited for patient cohorts, where per-patient aggregation provides more robust units for data integration. We use our metacells to reveal expression dynamics and gradual reconfiguration of the chromatin landscape during hematopoietic differentiation and to uniquely identify CD4 T cell differentiation and activation states associated with disease onset and severity in a Coronavirus Disease 2019 (COVID-19) patient cohort.

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  • All tested metacell approaches were suitable for downstream network analysis in the CD34+ hematopoietic stem and progenitor cell dataset.

    “We applied hdWGCNA to a dataset of CD34+ hematopoietic stem and progenitor stem cells16 using two additional metacell approaches14,16 and found that all approaches were suitable for downstream network analysis (Figure S2; Data S1).”
  • SEACells and Metacell2 do not account for cell labels in their aggregation procedures, which may result in a number of metacells containing transcriptomes from differently labeled cells.

    “Notably, SEACells and Metacell2 do not account for cell labels in their aggregation procedures, which may result in a number of metacells containing transcriptomes from differently labeled cells.”
  • To reduce the influence of stochastic DNA damage signal, single cells were grouped into 300 metacells based on transcriptome profiles using SEACell before the DNA damage-gene expression correlation analysis.

    “To minimize the influences from stochastic DNA damage signal, we used the SEACell software59 to group the single cells into 300 metacells based on transcriptome profiles.”

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Research works printed but not linked: 2

  1. [15]Bauckage, C., Kersting, K., Hoppe, F. & Thurau, C. in Workshop New Challenges in Neural Computation. https://www.techfak.uni-bielefeld.de/~fschleif/mlr/mlr_03_2015.pdf (2015).
  2. [18]McDaid, A. F., Greene, D. & Hurley, N. Normalized mutual information to evaluate overlapping community finding algorithms. Preprint at https://arxiv.org/abs/1110.2515 (2011). · arXiv

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Authors
Persad, S., Choo, Z.-N., Dien, C., Sohail, N., Masilionis, I., Chaligné, R., Nawy, T., Brown, C. C., Sharma, R., Pe’er, I., Setty, M., & Pe’er, D.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • Fred Hutch Cancer Center (US)
  • Columbia University (US)
Corresponding author
  • Pe’er, Itsik
  • Setty, Manu
  • Pe’er, Dana
Venue
Nature Biotechnology
Published
2023-03-27
Volume
41
Issue
12
Pages
1746-1757
ISSN
  • 0733-222X (ISSN-L)
  • 1087-0156
  • 1546-1696
OpenAlex
W4360999291
Cited by
222
References
72
Citations by year
2026: 72 · 2025: 54 · 2024: 72 · 2023: 20 · 2022: 3 · 2013: 1
FWCI
19.87
Type
journal article
Language
en
Open access
Locations
  • Nature Biotechnology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (R35 GM147125)
  • U.S. Department of Health & Human Services | NIH | National Cancer Institute (U54 CA209975, U2C CA233284)
  • Howard Hughes Medical Institute
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
metacells, transcriptional heterogeneity, chromatin accessibility, ATAC-seq, single-cell RNA sequencing, hematopoietic differentiation, CD4+ T cell activation, COVID-19 pandemic, data integration
MeSH terms
Algorithms, Chromatin, Humans, CD4-Positive T-Lymphocytes, Genomics, Epigenomics, Single-Cell Analysis

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