A comparative atlas of single-cell chromatin accessibility in the human brain
Keene C. Dirk Behrens M. Margarita Lein Ed S. Shapovalova Nadiya Hirschstein Daniel Linnarsson Sten Levi Boaz Wang Allen Li Yang Eric Preissl Sebastian Miller Michael Johnson Nicholas D. Jiao Henry Zhu Chenxu Kern Colin Tian Wei Siletti Kimberly Lucero Jacinta Yang Qian Zhu Quan Zemke Nathan Yanny Anna Marie Osteen Julia Ren Bing Pinto-Duarte Antonio Emerson Nora Espinoza Sarah Poirin Olivier Ecker Joseph R. Wang Zhaoning Dee Nick Wang Zihan Bakken Trygve E. Shang Jingbo Nyhus Julie Xie Yang Lin Lin Hodge Rebecca D. Casper Tamara
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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.引用本文复制引用
Keene C. Dirk,Behrens M. Margarita,Lein Ed S.,Shapovalova Nadiya,Hirschstein Daniel,Linnarsson Sten,Levi Boaz,Wang Allen,Li Yang Eric,Preissl Sebastian,Miller Michael,Johnson Nicholas D.,Jiao Henry,Zhu Chenxu,Kern Colin,Tian Wei,Siletti Kimberly,Lucero Jacinta,Yang Qian,Zhu Quan,Zemke Nathan,Yanny Anna Marie,Osteen Julia,Ren Bing,Pinto-Duarte Antonio,Emerson Nora,Espinoza Sarah,Poirin Olivier,Ecker Joseph R.,Wang Zhaoning,Dee Nick,Wang Zihan,Bakken Trygve E.,Shang Jingbo,Nyhus Julie,Xie Yang,Lin Lin,Hodge Rebecca D.,Casper Tamara.A comparative atlas of single-cell chromatin accessibility in the human brain[EB/OL].(2025-03-28)[2026-05-08].https://www.biorxiv.org/content/10.1101/2022.11.09.515833.学科分类
生物科学研究方法、生物科学研究技术/神经病学、精神病学/分子生物学
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