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

• Published in: Science (American Association for the Advancement of Science) Vol. 382; no. 6667; p. eadf7044
• Main Authors: Li, Yang Eric, Preissl, Sebastian, Miller, Michael, Johnson, Nicholas D., Wang, Zihan, Jiao, Henry, Zhu, Chenxu, Wang, Zhaoning, Xie, Yang, Poirion, Olivier, Kern, Colin, Pinto-Duarte, Antonio, Tian, Wei, Siletti, Kimberly, Emerson, Nora, Osteen, Julia, Lucero, Jacinta, Lin, Lin, Yang, Qian, Zhu, Quan, Zemke, Nathan, Espinoza, Sarah, Yanny, Anna Marie, Nyhus, Julie, Dee, Nick, Casper, Tamara, Shapovalova, Nadiya, Hirschstein, Daniel, Hodge, Rebecca D., Linnarsson, Sten, Bakken, Trygve, Levi, Boaz, Keene, C. Dirk, Shang, Jingbo, Lein, Ed, Wang, Allen, Behrens, M. Margarita, Ecker, Joseph R., Ren, Bing
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 13.10.2023
• Subjects: Accessibility; Animals; Annotations; Atlases as Topic; Brain; Brain - cytology; Brain - metabolism; Chromatin - metabolism; Chromatin remodeling; Coding; Conserved sequence; Disorders; DNA - metabolism; Etiology; Gene expression; Gene mapping; Gene regulation; Genomes; Health risks; Heterogeneity; Humans; Machine learning; Mental disorders; Meta Analysis; Mice; Neurons - metabolism; Non-coding RNA; Nucleotide sequence; Proteins; Regulatory sequences; Regulatory Sequences, Nucleic Acid - genetics; Risk; Sequences; Single-Cell Analysis
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.adf7044

Recent advances in single-cell transcriptomics have illuminated the diverse neuronal and glial cell types within the human brain. However, the regulatory programs governing cell identity and function remain unclear. Using a single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq), we explored open chromatin landscapes across 1.1 million cells in 42 brain regions from three adults. Integrating this data unveiled 107 distinct cell types and their specific utilization of 544,735 candidate cis-regulatory DNA elements (cCREs) in the human genome. Nearly a third of the cCREs demonstrated conservation and chromatin accessibility in the mouse brain cells. We reveal strong links between specific brain cell types and neuropsychiatric disorders including schizophrenia, bipolar disorder, Alzheimer’s disease (AD), and major depression, and have developed deep learning models to predict the regulatory roles of noncoding risk variants in these disorders.