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A comparative atlas of single-cell chromatin accessibility in the human brain

View ORCID ProfileYang Eric Li, View ORCID ProfileSebastian Preissl, View ORCID ProfileMichael Miller, View ORCID ProfileNicholas D. Johnson, View ORCID ProfileZihan Wang, Henry Jiao, View ORCID ProfileChenxu Zhu, View ORCID ProfileZhaoning Wang, View ORCID ProfileYang Xie, View ORCID ProfileOlivier Poirion, View ORCID ProfileColin Kern, View ORCID ProfileAntonio Pinto-Duarte, Wei Tian, Kimberly Siletti, Nora Emerson, Julia Osteen, View ORCID ProfileJacinta Lucero, Lin Lin, Qian Yang, View ORCID ProfileQuan Zhu, View ORCID ProfileSarah Espinoza, Anna Marie Yanny, Julie Nyhus, Nick Dee, Tamara Casper, Nadiya Shapovalova, Daniel Hirschstein, View ORCID ProfileRebecca D. Hodge, Sten Linnarsson, View ORCID ProfileTrygve Bakken, Boaz Levi, View ORCID ProfileC. Dirk Keene, Jingbo Shang, Ed S. Lein, View ORCID ProfileAllen Wang, View ORCID ProfileM. Margarita Behrens, View ORCID ProfileJoseph R. Ecker, View ORCID ProfileBing Ren
doi: https://doi.org/10.1101/2022.11.09.515833
Yang Eric Li
1Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, CA, USA
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Sebastian Preissl
2Center for Epigenomics, University of California San Diego, School of Medicine, La Jolla, CA, USA.
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Michael Miller
2Center for Epigenomics, University of California San Diego, School of Medicine, La Jolla, CA, USA.
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Nicholas D. Johnson
3The Salk Institute for Biological Studies, La Jolla, CA, USA
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Zihan Wang
4Department of Computer Science and Engineering, University of California San Diego, CA, USA
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Henry Jiao
2Center for Epigenomics, University of California San Diego, School of Medicine, La Jolla, CA, USA.
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Chenxu Zhu
1Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, CA, USA
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Zhaoning Wang
1Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, CA, USA
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Yang Xie
1Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, CA, USA
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Olivier Poirion
2Center for Epigenomics, University of California San Diego, School of Medicine, La Jolla, CA, USA.
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Colin Kern
2Center for Epigenomics, University of California San Diego, School of Medicine, La Jolla, CA, USA.
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Antonio Pinto-Duarte
3The Salk Institute for Biological Studies, La Jolla, CA, USA
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Wei Tian
3The Salk Institute for Biological Studies, La Jolla, CA, USA
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Kimberly Siletti
5Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
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Nora Emerson
3The Salk Institute for Biological Studies, La Jolla, CA, USA
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Julia Osteen
3The Salk Institute for Biological Studies, La Jolla, CA, USA
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Jacinta Lucero
3The Salk Institute for Biological Studies, La Jolla, CA, USA
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Lin Lin
2Center for Epigenomics, University of California San Diego, School of Medicine, La Jolla, CA, USA.
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Qian Yang
2Center for Epigenomics, University of California San Diego, School of Medicine, La Jolla, CA, USA.
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Quan Zhu
2Center for Epigenomics, University of California San Diego, School of Medicine, La Jolla, CA, USA.
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Sarah Espinoza
2Center for Epigenomics, University of California San Diego, School of Medicine, La Jolla, CA, USA.
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Anna Marie Yanny
6Allen Institute for Brain Science, Seattle, WA, USA
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Julie Nyhus
6Allen Institute for Brain Science, Seattle, WA, USA
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Nick Dee
6Allen Institute for Brain Science, Seattle, WA, USA
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Tamara Casper
6Allen Institute for Brain Science, Seattle, WA, USA
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Nadiya Shapovalova
6Allen Institute for Brain Science, Seattle, WA, USA
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Daniel Hirschstein
6Allen Institute for Brain Science, Seattle, WA, USA
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Rebecca D. Hodge
6Allen Institute for Brain Science, Seattle, WA, USA
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Sten Linnarsson
5Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
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Trygve Bakken
6Allen Institute for Brain Science, Seattle, WA, USA
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Boaz Levi
6Allen Institute for Brain Science, Seattle, WA, USA
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C. Dirk Keene
7Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA
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Jingbo Shang
4Department of Computer Science and Engineering, University of California San Diego, CA, USA
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Ed S. Lein
6Allen Institute for Brain Science, Seattle, WA, USA
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Allen Wang
2Center for Epigenomics, University of California San Diego, School of Medicine, La Jolla, CA, USA.
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M. Margarita Behrens
3The Salk Institute for Biological Studies, La Jolla, CA, USA
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Joseph R. Ecker
3The Salk Institute for Biological Studies, La Jolla, CA, USA
8Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA, USA
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Bing Ren
1Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, CA, USA
2Center for Epigenomics, University of California San Diego, School of Medicine, La Jolla, CA, USA.
9Ludwig Institute for Cancer Research, La Jolla, CA, USA
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  • For correspondence: biren@health.ucsd.edu
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Abstract

The human brain contains an extraordinarily diverse set of neuronal and glial cell types. Recent advances in single cell transcriptomics have begun to delineate the cellular heterogeneity in different brain regions, but the transcriptional regulatory programs responsible for the identity and function of each brain cell type remain to be defined. Here, we carried out single nucleus ATAC-seq analysis to probe the open chromatin landscape from over 1.1 million cells in 42 brain regions of three neurotypical adult donors. Integrative analysis of the resulting data identified 107 distinct cell types and revealed the cell-type-specific usage of 544,735 candidate cis-regulatory DNA elements (cCREs) in the human genome. Nearly 1/3 of them displayed sequence conservation as well as chromatin accessibility in the mouse brain. On the other hand, nearly 40% cCREs were human specific, with chromatin accessibility associated with species-restricted gene expression. Interestingly, these human specific cCREs were enriched for distinct families of retrotransposable elements, which displayed cell-type-specific chromatin accessibility. We uncovered strong associations between specific brain cell types and neuropsychiatric disorders. We futher developed deep learning models to predict regulatory function of non-coding disease risk variants.

Competing Interest Statement

J.R.E is a member of the scientific advisor for Zymo Research and Ionis. B.R. is a co-founder and consultant of Arima Genomics Inc. and co-founder of Epigenome Technologies.

Footnotes

  • http://catlas.org

  • http://catlas.org/humanbrain

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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A comparative atlas of single-cell chromatin accessibility in the human brain
Yang Eric Li, Sebastian Preissl, Michael Miller, Nicholas D. Johnson, Zihan Wang, Henry Jiao, Chenxu Zhu, Zhaoning Wang, Yang Xie, Olivier Poirion, Colin Kern, Antonio Pinto-Duarte, Wei Tian, Kimberly Siletti, Nora Emerson, Julia Osteen, Jacinta Lucero, Lin Lin, Qian Yang, Quan Zhu, Sarah Espinoza, Anna Marie Yanny, Julie Nyhus, Nick Dee, Tamara Casper, Nadiya Shapovalova, Daniel Hirschstein, Rebecca D. Hodge, Sten Linnarsson, Trygve Bakken, Boaz Levi, C. Dirk Keene, Jingbo Shang, Ed S. Lein, Allen Wang, M. Margarita Behrens, Joseph R. Ecker, Bing Ren
bioRxiv 2022.11.09.515833; doi: https://doi.org/10.1101/2022.11.09.515833
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A comparative atlas of single-cell chromatin accessibility in the human brain
Yang Eric Li, Sebastian Preissl, Michael Miller, Nicholas D. Johnson, Zihan Wang, Henry Jiao, Chenxu Zhu, Zhaoning Wang, Yang Xie, Olivier Poirion, Colin Kern, Antonio Pinto-Duarte, Wei Tian, Kimberly Siletti, Nora Emerson, Julia Osteen, Jacinta Lucero, Lin Lin, Qian Yang, Quan Zhu, Sarah Espinoza, Anna Marie Yanny, Julie Nyhus, Nick Dee, Tamara Casper, Nadiya Shapovalova, Daniel Hirschstein, Rebecca D. Hodge, Sten Linnarsson, Trygve Bakken, Boaz Levi, C. Dirk Keene, Jingbo Shang, Ed S. Lein, Allen Wang, M. Margarita Behrens, Joseph R. Ecker, Bing Ren
bioRxiv 2022.11.09.515833; doi: https://doi.org/10.1101/2022.11.09.515833

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