Brain-wide correspondence of neuronal epigenomics and distant projections
Author:
Zhou JingtianORCID, Zhang Zhuzhu, Wu May, Liu Hanqing, Pang Yan, Bartlett AnnaORCID, Peng Zihao, Ding Wubin, Rivkin Angeline, Lagos Will N., Williams Elora, Lee Cheng-Ta, Miyazaki Paula AssakuraORCID, Aldridge Andrew, Zeng Qiurui, Salinda J. L. Angelo, Claffey Naomi, Liem MichelleORCID, Fitzpatrick Conor, Boggeman Lara, Yao ZizhenORCID, Smith Kimberly A.ORCID, Tasic BosiljkaORCID, Altshul Jordan, Kenworthy Mia A., Valadon CynthiaORCID, Nery Joseph R.ORCID, Castanon Rosa G.ORCID, Patne Neelakshi S., Vu Minh, Rashid Mohammad, Jacobs Matthew, Ito Tony, Osteen Julia, Emerson NoraORCID, Lee JasperORCID, Cho Silvia, Rink JonORCID, Huang Hsiang-Hsuan, Pinto-Duartec AntónioORCID, Dominguez Bertha, Smith Jared B.ORCID, O’Connor Carolyn, Zeng HongkuiORCID, Chen Shengbo, Lee Kuo-FenORCID, Mukamel Eran A.ORCID, Jin XinORCID, Margarita Behrens M.ORCID, Ecker Joseph R.ORCID, Callaway Edward M.ORCID
Abstract
AbstractSingle-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.
Publisher
Springer Science and Business Media LLC
Subject
Multidisciplinary
Reference46 articles.
1. Armand, E. J., Li, J., Xie, F., Luo, C. & Mukamel, E. A. Single-cell sequencing of brain cell transcriptomes and epigenomes. Neuron 109, 11–26 (2021). 2. Zhang, Z. et al. Epigenomic diversity of cortical projection neurons in the mouse brain. Nature 598, 167–173 (2021). 3. Chen, X. et al. High-throughput mapping of long-range neuronal projection using in situ sequencing. Cell 179, 772–786 (2019). 4. Sun, Y.-C. et al. Integrating barcoded neuroanatomy with spatial transcriptional profiling enables identification of gene correlates of projections. Nat. Neurosci. 24, 873–885 (2021). 5. Economo, M. N. et al. Distinct descending motor cortex pathways and their roles in movement. Nature 563, 79–84 (2018).
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