Epigenomic diversity of cortical projection neurons in the mouse brain

Zhuzhu Zhang, Jingtian Zhou, Pengcheng Tan, Yan Pang, Angeline C. Rivkin, Megan A. Kirchgessner, Elora Williams, Cheng-Ta Lee, Hanqing Liu, Alexis D. Franklin, Paula Assakura Miyazaki, Anna Bartlett, Andrew I. Aldridge, Minh Vu, Lara Boggeman, Conor Fitzpatrick, Joseph R. Nery, Rosa G. Castanon, Mohammad Rashid, Matthew W. Jacobs, Tony Ito-Cole, Carolyn O’Connor, António Pinto-Duartec, Bertha Dominguez, Jared B. Smith, Sheng-Yong Niu, Kuo-Fen Lee, Xin Jin, Eran A. Mukamel, M. Margarita Behrens, Joseph R. Ecker () and Edward M. Callaway ()
Additional contact information
Zhuzhu Zhang: The Salk Institute for Biological Studies
Jingtian Zhou: The Salk Institute for Biological Studies
Pengcheng Tan: The Salk Institute for Biological Studies
Yan Pang: The Salk Institute for Biological Studies
Angeline C. Rivkin: The Salk Institute for Biological Studies
Megan A. Kirchgessner: The Salk Institute for Biological Studies
Elora Williams: The Salk Institute for Biological Studies
Cheng-Ta Lee: The Salk Institute for Biological Studies
Hanqing Liu: The Salk Institute for Biological Studies
Alexis D. Franklin: The Salk Institute for Biological Studies
Paula Assakura Miyazaki: The Salk Institute for Biological Studies
Anna Bartlett: The Salk Institute for Biological Studies
Andrew I. Aldridge: The Salk Institute for Biological Studies
Minh Vu: The Salk Institute for Biological Studies
Lara Boggeman: The Salk Institute for Biological Studies
Conor Fitzpatrick: The Salk Institute for Biological Studies
Joseph R. Nery: The Salk Institute for Biological Studies
Rosa G. Castanon: The Salk Institute for Biological Studies
Mohammad Rashid: The Salk Institute for Biological Studies
Matthew W. Jacobs: The Salk Institute for Biological Studies
Tony Ito-Cole: The Salk Institute for Biological Studies
Carolyn O’Connor: 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
Sheng-Yong Niu: The Salk Institute for Biological Studies
Kuo-Fen Lee: The Salk Institute for Biological Studies
Xin Jin: The Salk Institute for Biological Studies
Eran A. Mukamel: University of California, San Diego
M. Margarita Behrens: The Salk Institute for Biological Studies
Joseph R. Ecker: The Salk Institute for Biological Studies
Edward M. Callaway: The Salk Institute for Biological Studies

Nature, 2021, vol. 598, issue 7879, 167-173

Abstract: Abstract Neuronal cell types are classically defined by their molecular properties, anatomy and functions. Although recent advances in single-cell genomics have led to high-resolution molecular characterization of cell type diversity in the brain1, neuronal cell types are often studied out of the context of their anatomical properties. To improve our understanding of the relationship between molecular and anatomical features that define cortical neurons, here we combined retrograde labelling with single-nucleus DNA methylation sequencing to link neural epigenomic properties to projections. We examined 11,827 single neocortical neurons from 63 cortico-cortical and cortico-subcortical long-distance projections. Our results showed unique epigenetic signatures of projection neurons that correspond to their laminar and regional location and projection patterns. On the basis of their epigenomes, intra-telencephalic cells that project to different cortical targets could be further distinguished, and some layer 5 neurons that project to extra-telencephalic targets (L5 ET) formed separate clusters that aligned with their axonal projections. Such separation varied between cortical areas, which suggests that there are area-specific differences in L5 ET subtypes, which were further validated by anatomical studies. Notably, a population of cortico-cortical projection neurons clustered with L5 ET rather than intra-telencephalic neurons, which suggests that a population of L5 ET cortical neurons projects to both targets. We verified the existence of these neurons by dual retrograde labelling and anterograde tracing of cortico-cortical projection neurons, which revealed axon terminals in extra-telencephalic targets including the thalamus, superior colliculus and pons. These findings highlight the power of single-cell epigenomic approaches to connect the molecular properties of neurons with their anatomical and projection properties.

Date: 2021
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DOI: 10.1038/s41586-021-03223-w

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