Cited by 173Genomics and Chromatin DynamicsSingle-cell and spatial transcriptomicsChromatin Remodeling and Cancer

A comparative atlas of single-cell chromatin accessibility in the human brain

Open access
Li, Yang Eric, Preissl, Sebastian, Miller, Michael, Johnson, Nicholas D., Wang, Zihan, Jiao, Henry, Zhu, Chenxu, Wang, Zhaoning +31 more·2023·Science

Published version of a preprint

Abstract

Recent advances in single-cell transcriptomics have illuminated the diverse neuronal and glial cell types within the human brain. However, the regulatory programs governing cell identity and function remain unclear. Using a single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq), we explored open chromatin landscapes across 1.1 million cells in 42 brain regions from three adults. Integrating this data unveiled 107 distinct cell types and their specific utilization of 544,735 candidate cis-regulatory DNA elements (cCREs) in the human genome. Nearly a third of the cCREs demonstrated conservation and chromatin accessibility in the mouse brain cells. We reveal strong links between specific brain cell types and neuropsychiatric disorders including schizophrenia, bipolar disorder, Alzheimer’s disease (AD), and major depression, and have developed deep learning models to predict the regulatory roles of noncoding risk variants in these disorders.

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  • Brains were collected using highly optimized brain preparation methods with a mean postmortem interval of 7.0 h that enable exceptionally high-quality snRNA-seq, snATAC-seq and MERFISH profiling.

    “Brains were collected using highly optimized brain preparation methods (mean postmortem interval = 7.0 h; Extended Data Fig. 1b) that enable exceptionally high-quality snRNA-seq, snATAC–seq and MERFISH profiling17–19,23,36,37.”

    From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [36]

    The section “A single-cell chromatin accessibility atlas of human brains” (page unavailable) reports snATAC-seq profiling of dissected human brain regions and quality-control evidence for reliable data. Our copy does not give a mean postmortem interval of 7.0 hours or establish that the brain preparation methods enabled high-quality snRNA-seq and MERFISH profiling. (LLM, conf=0.84)

    Experimental — accuracy not yet measured
  • DNase-seq and ChIP-seq from ENCODE and the Epigenomics Roadmap and pseudo-bulk single-cell ATAC-seq from CATlas focus the model towards distal regulatory elements.

    “as well as DNase-seq and ChIP–seq from ENCODE and the Epigenomics Roadmap31,99 and pseudo-bulk single-cell ATAC–seq data from CATlas100,101, which focuses the model towards distal regulatory elements.”

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Research works printed but not linked: 1

  1. [75]Hodge RD, Bakken TE, Miller JA, Smith KA, Barkan ER, Graybuck LT, Close JL, Long B, Johansen N, Penn O, Yao Z, Eggermont J, Höllt T, Levi BP, Shehata SI, Aevermann B, Beller A, Bertagnolli D, Brouner K, Casper T, Cobbs C, Dalley R, Dee N, Ding S-L, Ellenbogen RG, Fong O, Garren E, Goldy J, Gwinn RP, Hirschstein D, Keene CD, Keshk M, Ko AL, Lathia K, Mahfouz A, Maltzer Z, McGraw M, Nguyen TN, Nyhus J, Ojemann JG, Oldre A, Parry S, Reynolds S, Rimorin C, Shapovalova NV, Somasundaram S, Szafer A, Thomsen ER, Tieu M, Quon G, Scheuermann RH, Yuste R, Sunkin SM, Lelieveldt B, Feng D, Ng L, Bernard A, Hawrylycz M, Phillips JW, Tasic B, Zeng H, Jones AR, Koch C, Lein ES, Conserved cell types with divergent features in human versus mouse cortex. Nature. 573, 61– 68 (2019). 31435019 PMC6919571

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Authors
Li, Y. E., Preissl, S., Miller, M., Johnson, N. D., Wang, Z., Jiao, H., Zhu, C., Wang, Z., Xie, Y., Poirion, O., Kern, C., Pinto-Duarte, A., Tian, W., Siletti, K., Emerson, N., Osteen, J., Lucero, J., Lin, L., Yang, Q., Zhu, Q., Zemke, N., Espinoza, S., Yanny, A. M., Nyhus, J., Dee, N., Casper, T., Shapovalova, N., Hirschstein, D., Hodge, R. D., Linnarsson, S., Bakken, T., Levi, B., Keene, C. D., Shang, J., Lein, E., Wang, A., Behrens, M. M., Ecker, J. R., & Ren, B.
Affiliations
  • University of California San Diego (US)
  • Salk Institute for Biological Studies (US)
  • The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
  • Karolinska Institutet (SE)
  • Allen Institute for Brain Science (US)
  • University of Washington (US)
Corresponding author
Ren, Bing
Venue
Science
Published
2023-10-13
Volume
382
Issue
6667
Pages
eadf7044-eadf7044
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
OpenAlex
W4387568435
Cited by
173
References
140
Citations by year
2026: 55 · 2025: 68 · 2024: 43 · 2023: 7
FWCI
15.42
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Science (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Science Foundation (2040727)
  • Nancy and Buster Alvord Endowment
  • University of Washington
  • Life Sciences Research Foundation
  • National Institutes of Health (5u01mh114812-03, 1s10od026929-01, Bridge2AI, U01MH114812)
  • University of California, San Diego (#S10 OD026929)
  • Department of Laboratory Medicine and Pathology, University of Washington
  • National Institute of Mental Health (U01MH114828, U01MH114812, UM1MH130994)
  • National Human Genome Research Institute (U54HG012510)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
single-cell chromatin accessibility, human brain, snATAC-seq, brain cell types, neuropsychiatric disorders, schizophrenia, bipolar disorder, Alzheimer's disease, major depressive disorder, deep learning prediction
MeSH terms
Animals, Atlases as Topic, Brain, Chromatin, DNA, Humans, Neurons, Regulatory Sequences, Nucleic Acid, Mice, Single-Cell Analysis

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