Cited by 344Single-cell and spatial transcriptomicsGenomics and Chromatin DynamicsChromatin Remodeling and Cancer

An ultra high-throughput method for single-cell joint analysis of open chromatin and transcriptome

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Zhu, Chenxu, Yu, Miao, Huang, Hui, Juric, Ivan, Abnousi, Armen, Hu, Rong, Lucero, Jacinta, Behrens, M. Margarita +2 more·2019·Nature Structural & Molecular Biology

Abstract

Simultaneous profiling of transcriptome and chromatin accessibility within single cells is a powerful approach to dissect gene regulatory programs in complex tissues. However, current tools are limited by modest throughput. We now describe an ultra high-throughput method, Paired-seq, for parallel analysis of transcriptome and accessible chromatin in millions of single cells. We demonstrate the utility of Paired-seq for analyzing the dynamic and cell-type-specific gene regulatory programs in complex tissues by applying it to mouse adult cerebral cortex and fetal forebrain. The joint profiles of a large number of single cells allowed us to deconvolute the transcriptome and open chromatin landscapes in the major cell types within these brain tissues, infer putative target genes of candidate enhancers, and reconstruct the trajectory of cellular lineages within the developing forebrain.

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  • Compared to prior single-cell multiomics sequencing methods for joint RNA and epigenome analyses, Paired-Damage-seq displayed similar sensitivity in RNA detection.

    “Compared to prior single-cell multiomics sequencing methods for joint RNA and epigenome analyses27,39–41, Paired-Damage-seq displayed similar sensitivity in RNA detection, despite different DNA modalities being measured”
  • 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].”
  • Joint snRNA-seq and snATAC-seq on more than 15,000 fetal and adult mouse cortical cells showed dynamic, cell-type-specific changes in promoter accessibility during development.

    “Paired snRNA-seq and snATAC-seq of over 15,000 cells in fetal and adult mouse cortex revealed cell type-specific dynamic regulation of promoter accessibility during brain development (Chen et al., 2019b; Zhu et al., 2019).”

    From Single-Cell Sequencing of Brain Cell Transcriptomes and Epigenomes (2021) · cites this paper as Zhu et al., 2019

  • In mouse cerebral cortex, high-throughput multi-omics detected only 9-22 cell types, whereas scRNA-seq detected more than 100.

    “As a result, high-throughput multi-omics studies in mouse cerebral cortex identified 9–22 cell types (Chen et al., 2019b; Zhu et al., 2019), compared with over 100 cell types found using scRNA-seq (Tasic et al., 2018; Yao et al., 2020a, 2020b).”

    From Single-Cell Sequencing of Brain Cell Transcriptomes and Epigenomes (2021) · cites this paper as Zhu et al., 2019

  • Paired-seq used three rounds of ligation-based combinatorial indexing to process 1 million nuclei in a single experiment for parallel transcriptome and chromatin accessibility analyses.

    “This strategy was implemented shortly after by Paired-seq, which used three rounds of ligation-based combinatorial indexing to process 1 million nuclei in a single experiment for parallel transcriptome and chromatin accessibility analyses59.”

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Research works printed but not linked: 4

  1. [37]Lee D-S Single-cell multi-omic profiling of chromatin conformation and DNA methylome. bioRxiv, 503235 (2018).
  2. [41]Chen S, Lake BB & Zhang K Linking transcriptome and chromatin accessibility in nanoliter droplets for single-cell sequencing. bioRxiv, 692608 (2019).
  3. [46]Fang R Fast and Accurate Clustering of Single Cell Epigenomes Reveals <em>Cis</em>-Regulatory Elements in Rare Cell Types. bioRxiv, 615179 (2019).
  4. [52]Gorkin DU An atlas of dynamic chromatin landscapes in the developing mouse fetus. Nature (In Press).

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Authors
Zhu, C., Yu, M., Huang, H., Juric, I., Abnousi, A., Hu, R., Lucero, J., Behrens, M. M., Hu, M., & Ren, B.
Affiliations
  • Ludwig Cancer Research (US)
  • University of California San Diego (US)
  • Cleveland Clinic (US)
  • Salk Institute for Biological Studies (US)
Corresponding author
Ren, Bing
Venue
Nature Structural & Molecular Biology
Published
2019-11
Volume
26
Issue
11
Pages
1063-1070
ISSN
  • 1545-9985 (ISSN-L)
  • 1545-9993
OpenAlex
W2985765936
Cited by
344
References
71
Citations by year
2026: 30 · 2025: 47 · 2024: 56 · 2023: 66 · 2022: 56 · 2021: 56 · 2020: 31 · 2019: 1
FWCI
11.91
Type
journal article
Language
en
Open access
Locations
  • Nature Structural & Molecular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institute of Mental Health (U19MH114831)
  • National Human Genome Research Institute (U54HG006997)
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 › Chromatin Remodeling and Cancer
Keywords
single-cell transcriptomics, chromatin accessibility, open chromatin, enhancer target genes, gene regulatory programs, forebrain development, cerebral cortex
MeSH terms
Animals, Brain, Chromatin, Humans, Male, Mice, Inbred C57BL, Gene Expression Profiling, NIH 3T3 Cells, Mice, Hep G2 Cells, HEK293 Cells, Single-Cell Analysis, Transcriptome

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