Abstract
The 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 transcriptomics2–6 and high-throughput imaging technologies7,8 have 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 candidate cis-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 the cis-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.
Highlights
As part of the BRAIN Initiative Cell Census Network (BICCN), we performed single-nucleusATAC-seq assays using single-cell combinatorial indexingATAC-seq[17,25] for more than 800,000 cells from 45 dissected regions in the adult mouse brain to produce comprehensive maps of cCREs in distinct cerebral cell types
We calculated a regional specificity score for each subclass and cell type based on the contribution from different brain regions and showed that this score is highly consistent between biological replicates (Fig. 1f, g, Extended Data Fig. 12d, Methods)
We found good agreement between the regional specificity of most neuronal cell types defined using snATAC-seq datasets and the normalized in situ hybridization (ISH) signals of marker genes in each cell type (Extended Data Fig. 13, Supplementary Table 6, Methods)
Summary
Because most neuronal types showed highly restricted distribution in the mouse cerebral cortex and basal ganglia, we hypothesized that the regional specificity of different cell types is accompanied by differences in chromatin accessibility at the cCREs, which drive cell-specific gene expression patterns. We found a strong motif enrichment of the zinc-finger transcription factor family KLF in cCREs in SSTGA10 cells ( known as Sst-Chodl cells) compared with other SST neurons (Fig. 3c). We further performed motif analysis for differentially accessible regions in the ASCN cell type, finding enrichment of the binding motif for the GLI family of zinc-finger transcription factors (Fig. 3g, h, Extended Data Fig. 18f, Supplementary Table 14), which mediate the sonic hedgehog (Shh) signalling pathway that maintains neural stem-cell and astrocyte functions[36]. We first connected 261,204 distal cCREs to 12,722 putative target genes by measuring the co-accessibility using Cicero[37,38] (Fig. 4a, Methods) This analysis identified a total of 813,638 gene–cCRE pairs within 500 kb of each other (Supplementary Table 16). We identified the subset of cCREs that might increase the a Cell types of SSTGA coloured by type
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