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Cited by 139Epigenetics and DNA MethylationSingle-cell and spatial transcriptomicsGenomics and Chromatin Dynamics

Single-cell DNA methylome and 3D multi-omic atlas of the adult mouse brain

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Liu, Hanqing, Zeng, Qiurui, Zhou, Jingtian, Bartlett, Anna, Wang, Bang-An, Berube, Peter, Tian, Wei, Kenworthy, Mia +26 more·2023·Nature
DOI 10.1038/s41586-023-06805-yPMC PMC10719113

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Abstract

Abstract Cytosine DNA methylation is essential in brain development and is implicated in various neurological disorders. Understanding DNA methylation diversity across the entire brain in a spatial context is fundamental for a complete molecular atlas of brain cell types and their gene regulatory landscapes. Here we used single-nucleus methylome sequencing (snmC-seq3) and multi-omic sequencing (snm3C-seq) 1 technologies to generate 301,626 methylomes and 176,003 chromatin conformation–methylome joint profiles from 117 dissected regions throughout the adult mouse brain. Using iterative clustering and integrating with companion whole-brain transcriptome and chromatin accessibility datasets, we constructed a methylation-based cell taxonomy with 4,673 cell groups and 274 cross-modality-annotated subclasses. We identified 2.6 million differentially methylated regions across the genome that represent potential gene regulation elements. Notably, we observed spatial cytosine methylation patterns on both genes and regulatory elements in cell types within and across brain regions. Brain-wide spatial transcriptomics data validated the association of spatial epigenetic diversity with transcription and improved the anatomical mapping of our epigenetic datasets. Furthermore, chromatin conformation diversities occurred in important neuronal genes and were highly associated with DNA methylation and transcription changes. Brain-wide cell-type comparisons enabled the construction of regulatory networks that incorporate transcription factors, regulatory elements and their potential downstream gene targets. Finally, intragenic DNA methylation and chromatin conformation patterns predicted alternative gene isoform expression observed in a whole-brain SMART-seq 2 dataset. Our study establishes a brain-wide, single-cell DNA methylome and 3D multi-omic atlas and provides a valuable resource for comprehending the cellular–spatial and regulatory genome diversity of the mouse brain.

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  • Each cell category within the body and the brain possesses a distinct epigenome.

    “given that each cell category within the body and the brain possesses a distinct epigenome [475,476]”

    From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [475]

    The Cell-type-specific regulatory elements section reports cell-type-specific DNA methylation and chromatin accessibility across brain cell subclasses, supporting the brain portion of the claim. The study examines the adult mouse brain, not cell categories throughout the body, and does not establish that every category has a distinct epigenome. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

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Authors
Liu, H., Zeng, Q., Zhou, J., Bartlett, A., Wang, B.-A., Berube, P., Tian, W., Kenworthy, M., Altshul, J., Nery, J. R., Chen, H., Castanon, R. G., Zu, S., Li, Y. E., Lucero, J., Osteen, J. K., Pinto-Duarte, A., Lee, J., Rink, J., Cho, S., Emerson, N., Nunn, M., O’Connor, C., Wu, Z., Stoica, I., Yao, Z., Smith, K. A., Tasic, B., Luo, C., Dixon, J. R., Zeng, H., Ren, B., Behrens, M. M., & Ecker, J. R.
Affiliations
  • Salk Institute for Biological Studies (US)
  • University of California San Diego (US)
  • University of California, Berkeley (US)
  • Allen Institute for Brain Science (US)
  • University of California, Los Angeles (US)
Corresponding author
Ecker, Joseph R.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2023-12-13
Volume
624
Issue
7991
Pages
366-377
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-023-06805-y
PMC
PMC10719113
OpenAlex
W4389670293
Cited by
139
References
26
Citations by year
2026: 35 · 2025: 63 · 2024: 32 · 2023: 9
FWCI
12.65
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • National Institutes of Health (1s10od023689-01a1)
  • National Institute of Mental Health (U19MH114831, U19MH114830)
  • National Cancer Institute (P30CA014195)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • 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
Keywords
DNA methylation, adult mouse brain, chromatin conformation, brain cell types, differentially methylated regions, chromatin accessibility, gene regulatory networks, spatial transcriptomics

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