An atlas of gene regulatory elements in adult mouse cerebrum

• DOI: 10.1038/s41586-021-03604-1
• Publication Date: 2021-10-07T08:22:58Z
• Authors: Yang Eric Li; Sebastian Preissl; Xiaomeng Hou; Ziyang Zhang; Kai Zhang; Yunjiang Qiu; Olivier B. Poirion; Bin Li; Joshua Chiou; Hanqing Liu; Antonio Pinto-Duarte; Naoki Kubo; Xiaoyu Yang; Rongxin Fang; Xinxin Wang; Jee Yun Han; Jacinta Lucero; Yiming Yan; Michael Miller; Samantha Kuan; David Gorkin; Kyle J. Gaulton; Yin Shen; Michael Nunn; Eran A. Mukamel; M. Margarita Behrens; Joseph R. Ecker; Bing Ren
• Keywords: Male; 0301 basic medicine; General Science & Technology; 1.1 Normal biological development and functioning; 610; Regulatory Sequences, Nucleic Acid; Inbred C57BL; Article; Mice; 03 medical and health sciences; Atlases as Topic; Underpinning research; Genetics; Animals; Humans; Genetic Predisposition to Disease; Cerebrum; Neurons; Nucleic Acid; Human Genome; Neurosciences; DNA; Sequence Analysis, DNA; Stem Cell Research; Chromatin Assembly and Disassembly; Chromatin; Brain Disorders; Mice, Inbred C57BL; Gene Expression Regulation; Neurological; Stem Cell Research - Nonembryonic - Non-Human; Nervous System Diseases; Single-Cell Analysis; Regulatory Sequences; Sequence Analysis; Neuroglia; Biotechnology

AbstractThe mammalian cerebrum performs high-level sensory perception, motor control and cognitive functions through highly specialized cortical and subcortical structures1. Recent surveys of mouse and human brains with single-cell transcriptomics2–6and high-throughput imaging technologies7,8have uncovered hundreds of neural cell types distributed in different brain regions, but the transcriptional regulatory programs that are responsible for the unique identity and function of each cell type remain unknown. Here we probe the accessible chromatin in more than 800,000 individual nuclei from 45 regions that span the adult mouse isocortex, olfactory bulb, hippocampus and cerebral nuclei, and use the resulting data to map the state of 491,818 candidatecis-regulatory DNA elements in 160 distinct cell types. We find high specificity of spatial distribution for not only excitatory neurons, but also most classes of inhibitory neurons and a subset of glial cell types. We characterize the gene regulatory sequences associated with the regional specificity within these cell types. We further link a considerable fraction of thecis-regulatory elements to putative target genes expressed in diverse cerebral cell types and predict transcriptional regulators that are involved in a broad spectrum of molecular and cellular pathways in different neuronal and glial cell populations. Our results provide a foundation for comprehensive analysis of gene regulatory programs of the mammalian brain and assist in the interpretation of noncoding risk variants associated with various neurological diseases and traits in humans.