Brain-wide correspondence of neuronal epigenomics and distant projections

Jingtian Zhou, Zhuzhu Zhang, May Wu, Hanqing Liu, Yan Pang, Anna Bartlett, Zihao Peng, Wubin Ding, Angeline Rivkin, Will N. Lagos, Elora Williams, Cheng-Ta Lee, Paula Assakura Miyazaki, Andrew Aldridge, Qiurui Zeng, J. L. Angelo Salinda, Naomi Claffey, Michelle Liem, Conor Fitzpatrick, Lara Boggeman, Zizhen Yao, Kimberly A. Smith, Bosiljka Tasic, Jordan Altshul, Mia A. Kenworthy, Cynthia Valadon, Joseph R. Nery, Rosa G. Castanon, Neelakshi S. Patne, Minh Vu, Mohammad Rashid, Matthew Jacobs, Tony Ito, Julia Osteen, Nora Emerson, Jasper Lee, Silvia Cho, Jon Rink, Hsiang-Hsuan Huang, António Pinto-Duartec, Bertha Dominguez, Jared B. Smith, Carolyn O’Connor, Hongkui Zeng, Shengbo Chen, Kuo-Fen Lee, Eran A. Mukamel, Xin Jin, M. Margarita Behrens, Joseph R. Ecker () and Edward M. Callaway ()
Additional contact information
Jingtian Zhou: The Salk Institute for Biological Studies
Zhuzhu Zhang: The Salk Institute for Biological Studies
May Wu: The Salk Institute for Biological Studies
Hanqing Liu: The Salk Institute for Biological Studies
Yan Pang: The Salk Institute for Biological Studies
Anna Bartlett: The Salk Institute for Biological Studies
Zihao Peng: Nanchang University
Wubin Ding: The Salk Institute for Biological Studies
Angeline Rivkin: The Salk Institute for Biological Studies
Will N. Lagos: The Salk Institute for Biological Studies
Elora Williams: The Salk Institute for Biological Studies
Cheng-Ta Lee: The Salk Institute for Biological Studies
Paula Assakura Miyazaki: The Salk Institute for Biological Studies
Andrew Aldridge: The Salk Institute for Biological Studies
Qiurui Zeng: The Salk Institute for Biological Studies
J. L. Angelo Salinda: The Salk Institute for Biological Studies
Naomi Claffey: Flow Cytometry Core Facility, The Salk Institute for Biological Studies
Michelle Liem: Flow Cytometry Core Facility, The Salk Institute for Biological Studies
Conor Fitzpatrick: Flow Cytometry Core Facility, The Salk Institute for Biological Studies
Lara Boggeman: Flow Cytometry Core Facility, The Salk Institute for Biological Studies
Zizhen Yao: Allen Institute for Brain Science
Kimberly A. Smith: Allen Institute for Brain Science
Bosiljka Tasic: Allen Institute for Brain Science
Jordan Altshul: The Salk Institute for Biological Studies
Mia A. Kenworthy: The Salk Institute for Biological Studies
Cynthia Valadon: The Salk Institute for Biological Studies
Joseph R. Nery: The Salk Institute for Biological Studies
Rosa G. Castanon: The Salk Institute for Biological Studies
Neelakshi S. Patne: The Salk Institute for Biological Studies
Minh Vu: The Salk Institute for Biological Studies
Mohammad Rashid: The Salk Institute for Biological Studies
Matthew Jacobs: The Salk Institute for Biological Studies
Tony Ito: The Salk Institute for Biological Studies
Julia Osteen: The Salk Institute for Biological Studies
Nora Emerson: The Salk Institute for Biological Studies
Jasper Lee: The Salk Institute for Biological Studies
Silvia Cho: The Salk Institute for Biological Studies
Jon Rink: The Salk Institute for Biological Studies
Hsiang-Hsuan Huang: The Salk Institute for Biological Studies
António Pinto-Duartec: The Salk Institute for Biological Studies
Bertha Dominguez: The Salk Institute for Biological Studies
Jared B. Smith: The Salk Institute for Biological Studies
Carolyn O’Connor: Flow Cytometry Core Facility, The Salk Institute for Biological Studies
Hongkui Zeng: Allen Institute for Brain Science
Shengbo Chen: Henan Engineering Research Center of Intelligent Technology and Application, Henan University
Kuo-Fen Lee: The Salk Institute for Biological Studies
Eran A. Mukamel: University of California San Diego
Xin Jin: East China Normal University
M. Margarita Behrens: The Salk Institute for Biological Studies
Joseph R. Ecker: The Salk Institute for Biological Studies
Edward M. Callaway: University of California San Diego

Nature, 2023, vol. 624, issue 7991, 355-365

Abstract: Abstract Single-cell analyses parse the brain’s billions of neurons into thousands of ‘cell-type’ clusters residing in different brain structures1. Many cell types mediate their functions through targeted long-distance projections allowing interactions between specific cell types. Here we used epi-retro-seq2 to link single-cell epigenomes and cell types to long-distance projections for 33,034 neurons dissected from 32 different regions projecting to 24 different targets (225 source-to-target combinations) across the whole mouse brain. We highlight uses of these data for interrogating principles relating projection types to transcriptomics and epigenomics, and for addressing hypotheses about cell types and connections related to genetics. We provide an overall synthesis with 926 statistical comparisons of discriminability of neurons projecting to each target for every source. We integrate this dataset into the larger BRAIN Initiative Cell Census Network atlas, composed of millions of neurons, to link projection cell types to consensus clusters. Integration with spatial transcriptomics further assigns projection-enriched clusters to smaller source regions than the original dissections. We exemplify this by presenting in-depth analyses of projection neurons from the hypothalamus, thalamus, hindbrain, amygdala and midbrain to provide insights into properties of those cell types, including differentially expressed genes, their associated cis-regulatory elements and transcription-factor-binding motifs, and neurotransmitter use.

Date: 2023
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DOI: 10.1038/s41586-023-06823-w

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