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

Hanqing Liu, Jingtian Zhou, Wei Tian, Chongyuan Luo, Anna Bartlett, Andrew Aldridge, Jacinta Lucero, Julia K. Osteen, Joseph R. Nery, Huaming Chen, Angeline Rivkin, Rosa G. Castanon, Ben Clock, Yang Eric Li, Xiaomeng Hou, Olivier B. Poirion, Sebastian Preissl, Antonio Pinto-Duarte, Carolyn O’Connor, Lara Boggeman, Conor Fitzpatrick, Michael Nunn, Eran A. Mukamel, Zhuzhu Zhang, Edward M. Callaway, Bing Ren, Jesse R. Dixon, M. Margarita Behrens and Joseph R. Ecker ()
Additional contact information
Hanqing Liu: The Salk Institute for Biological Studies
Jingtian Zhou: The Salk Institute for Biological Studies
Wei Tian: The Salk Institute for Biological Studies
Chongyuan Luo: The Salk Institute for Biological Studies
Anna Bartlett: The Salk Institute for Biological Studies
Andrew Aldridge: The Salk Institute for Biological Studies
Jacinta Lucero: The Salk Institute for Biological Studies
Julia K. Osteen: The Salk Institute for Biological Studies
Joseph R. Nery: The Salk Institute for Biological Studies
Huaming Chen: The Salk Institute for Biological Studies
Angeline Rivkin: The Salk Institute for Biological Studies
Rosa G. Castanon: The Salk Institute for Biological Studies
Ben Clock: The Salk Institute for Biological Studies
Yang Eric Li: Ludwig Institute for Cancer Research
Xiaomeng Hou: University of California, San Diego School of Medicine
Olivier B. Poirion: University of California, San Diego School of Medicine
Sebastian Preissl: University of California, San Diego School of Medicine
Antonio Pinto-Duarte: The Salk Institute for Biological Studies
Carolyn O’Connor: The Salk Institute for Biological Studies
Lara Boggeman: The Salk Institute for Biological Studies
Conor Fitzpatrick: The Salk Institute for Biological Studies
Michael Nunn: The Salk Institute for Biological Studies
Eran A. Mukamel: University of California, San Diego
Zhuzhu Zhang: The Salk Institute for Biological Studies
Edward M. Callaway: The Salk Institute for Biological Studies
Bing Ren: Ludwig Institute for Cancer Research
Jesse R. Dixon: The Salk Institute for Biological Studies
M. Margarita Behrens: The Salk Institute for Biological Studies
Joseph R. Ecker: The Salk Institute for Biological Studies

Nature, 2021, vol. 598, issue 7879, 120-128

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 sequencing1,2 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 data3 enabled prediction of high-confidence enhancer–gene interactions for all identified cell types, which were subsequently validated by cell-type-specific chromatin conformation capture experiments4. 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.

Date: 2021
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DOI: 10.1038/s41586-020-03182-8

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