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

Hanqing Liu, Qiurui Zeng, Jingtian Zhou, Anna Bartlett, Bang-An Wang, Peter Berube, Wei Tian, Mia Kenworthy, Jordan Altshul, Joseph R. Nery, Huaming Chen, Rosa G. Castanon, Songpeng Zu, Yang Eric Li, Jacinta Lucero, Julia K. Osteen, Antonio Pinto-Duarte, Jasper Lee, Jon Rink, Silvia Cho, Nora Emerson, Michael Nunn, Carolyn O’Connor, Zhanghao Wu, Ion Stoica, Zizhen Yao, Kimberly A. Smith, Bosiljka Tasic, Chongyuan Luo, Jesse R. Dixon, Hongkui Zeng, Bing Ren, M. Margarita Behrens and Joseph R. Ecker ()
Additional contact information
Hanqing Liu: The Salk Institute for Biological Studies
Qiurui Zeng: The Salk Institute for Biological Studies
Jingtian Zhou: The Salk Institute for Biological Studies
Anna Bartlett: The Salk Institute for Biological Studies
Bang-An Wang: The Salk Institute for Biological Studies
Peter Berube: The Salk Institute for Biological Studies
Wei Tian: The Salk Institute for Biological Studies
Mia Kenworthy: The Salk Institute for Biological Studies
Jordan Altshul: The Salk Institute for Biological Studies
Joseph R. Nery: The Salk Institute for Biological Studies
Huaming Chen: The Salk Institute for Biological Studies
Rosa G. Castanon: The Salk Institute for Biological Studies
Songpeng Zu: University of California, San Diego School of Medicine
Yang Eric Li: University of California, San Diego School of Medicine
Jacinta Lucero: The Salk Institute for Biological Studies
Julia K. Osteen: The Salk Institute for Biological Studies
Antonio Pinto-Duarte: The Salk Institute for Biological Studies
Jasper Lee: The Salk Institute for Biological Studies
Jon Rink: The Salk Institute for Biological Studies
Silvia Cho: The Salk Institute for Biological Studies
Nora Emerson: The Salk Institute for Biological Studies
Michael Nunn: The Salk Institute for Biological Studies
Carolyn O’Connor: The Salk Institute for Biological Studies
Zhanghao Wu: University of California, Berkeley
Ion Stoica: University of California, Berkeley
Zizhen Yao: Allen Institute for Brain Science
Kimberly A. Smith: Allen Institute for Brain Science
Bosiljka Tasic: Allen Institute for Brain Science
Chongyuan Luo: University of California, Los Angeles
Jesse R. Dixon: The Salk Institute for Biological Studies
Hongkui Zeng: Allen Institute for Brain Science
Bing Ren: University of California, San Diego School of Medicine
M. Margarita Behrens: The Salk Institute for Biological Studies
Joseph R. Ecker: The Salk Institute for Biological Studies

Nature, 2023, vol. 624, issue 7991, 366-377

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-seq2 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.

Date: 2023
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DOI: 10.1038/s41586-023-06805-y

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