Cited by 301Single-cell and spatial transcriptomicsEpigenetics and DNA MethylationGenomics and Chromatin Dynamics

DNA methylation atlas of the mouse brain at single-cell resolution

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Liu, Hanqing, Zhou, Jingtian, Tian, Wei, Luo, Chongyuan, Bartlett, Anna, Aldridge, Andrew, Lucero, Jacinta, Osteen, Julia K. +21 more·2021·Nature

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Abstract

Abstract Mammalian brain cells show remarkable diversity in gene expression, anatomy and function, yet the regulatory DNA landscape underlying this extensive heterogeneity is poorly understood. Here we carry out a comprehensive assessment of the epigenomes of mouse brain cell types by applying single-nucleus DNA methylation sequencing 1,2 to profile 103,982 nuclei (including 95,815 neurons and 8,167 non-neuronal cells) from 45 regions of the mouse cortex, hippocampus, striatum, pallidum and olfactory areas. We identified 161 cell clusters with distinct spatial locations and projection targets. We constructed taxonomies of these epigenetic types, annotated with signature genes, regulatory elements and transcription factors. These features indicate the potential regulatory landscape supporting the assignment of putative cell types and reveal repetitive usage of regulators in excitatory and inhibitory cells for determining subtypes. The DNA methylation landscape of excitatory neurons in the cortex and hippocampus varied continuously along spatial gradients. Using this deep dataset, we constructed an artificial neural network model that precisely predicts single neuron cell-type identity and brain area spatial location. Integration of high-resolution DNA methylomes with single-nucleus chromatin accessibility data 3 enabled prediction of high-confidence enhancer–gene interactions for all identified cell types, which were subsequently validated by cell-type-specific chromatin conformation capture experiments 4 . By combining multi-omic datasets (DNA methylation, chromatin contacts, and open chromatin) from single nuclei and annotating the regulatory genome of hundreds of cell types in the mouse brain, our DNA methylation atlas establishes the epigenetic basis for neuronal diversity and spatial organization throughout the mouse cerebrum.

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  • A different integration method (Allcools) gave similar clustering results.

    “A different integration method (Allcools)38 gave similar clustering results”

    From Molecular and spatial signatures of mouse brain aging at single-cell resolution (2023) · cites this paper as [38]

    The Methods section on clustering-related methods describes integration with Scanorama and subsequent co-clustering, but does not report a comparison with Allcools. A search for Allcools found it in the Methods section on cell-type-specific regulatory elements, where it was used to generate a methylation profile, not to compare clustering results. Page numbers are unavailable in our copy. (LLM, conf=0.74)

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Authors
Liu, H., Zhou, J., Tian, W., Luo, C., Bartlett, A., Aldridge, A., Lucero, J., Osteen, J. K., Nery, J. R., Chen, H., Rivkin, A., Castanon, R. G., Clock, B., Li, Y. E., Hou, X., Poirion, O. B., Preissl, S., Pinto-Duarte, A., O’Connor, C., Boggeman, L., Fitzpatrick, C., Nunn, M., Mukamel, E. A., Zhang, Z., Callaway, E. M., Ren, B., Dixon, J. R., Behrens, M. M., & Ecker, J. R.
Affiliations
  • Salk Institute for Biological Studies (US)
  • Ludwig Cancer Research (US)
  • University of California San Diego (US)
Corresponding author
Ecker, Joseph R.
Venue
Nature
Published
2021-10-06
Volume
598
Issue
7879
Pages
120-128
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W3203959602
Cited by
289
References
102
Citations by year
2026: 50 · 2025: 66 · 2024: 59 · 2023: 52 · 2022: 46 · 2021: 14 · 2020: 2
FWCI
14.21
Type
journal article
Language
en
Open access
Locations
  • Nature (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Institutes of Health (NCI CCSG: P30 014195, P30 014195, 1s10od023689-01a1)
  • National Institute of Mental Health (U19MH114831, U19MH114830, F30MH011483)
  • National Human Genome Research Institute (R01HG010634)
  • National Cancer Institute (S10-OD023689, CCSG:P30 014195, NIH-NCI CCSG: P30 014195, P30014195, P30CA014195)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
DNA methylation, mouse brain, neuronal cell types, excitatory and inhibitory neurons, enhancer-gene interactions, chromatin accessibility, hippocampus, cerebral cortex, olfactory bulb, striatum, globus pallidus, transcription factors, regulatory elements
MeSH terms
Epigenome, Animals, Atlases as Topic, Brain, Chromatin, Cytosine, Enhancer Elements, Genetic, Hippocampus, Male, Mice, Inbred C57BL, Models, Biological, Neural Pathways, Neurons, Dentate Gyrus, DNA Methylation, Gene Expression Profiling, Mice, Epigenomics, Single-Cell Analysis, Datasets as Topic

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