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

• DOI: 10.1126/science.adf7044
• Publication Date: 2023-10-12T18:00:31Z
• Authors: 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; Nathan Zemke; 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 Lein; Allen Wang; M. Margarita Behrens; Joseph R. Ecker; Bing Ren
• Keywords: Neurons; Nucleic Acid; 610; Brain; DNA; Regulatory Sequences, Nucleic Acid; Chromatin; 3. Good health; Mice; Atlases as Topic; Animals; Humans; Single-Cell Analysis; Regulatory Sequences

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.