An atlas of gene regulatory elements in adult mouse cerebrum

The mammalian cerebrum performs high-level sensory perception, motor control and cognitive functionsthrough highly specialized cortical and subcortical structures(1). Recent surveys of mouse and human brains with single-cell transcriptomics(2-6) and high-throughput imaging technologies(7,8) have uncovered hundreds of neural cell types distributed in different brain regions, but the transcriptional regulatory programsthat are responsible forthe 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 regionsthat 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 ofglial cell types. We characterize the gene regulatory sequences associated with the regional specificity within these cell types. We further link a considerable fraction ofthe cis-regulatory elementsto putative targetgenes expressed in diverse cerebral cell types and predict transcriptional regulatorsthat 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 ofgene regulatory programs ofthe mammalian brain and assist in the interpretation of noncoding riskvariants associated with various neurological diseases and traits in humans.

Automated summary

Recent studies have identified hundreds of neural cell types in different brain regions of mice and humans, but the transcriptional regulatory programs responsible for the unique identity and function of each cell type remain unknown. By analyzing the chromatin accessibility in individual nuclei from various brain regions, researchers have mapped candidate cis-regulatory DNA elements in distinct cell types, providing insights into the gene regulatory programs of the mammalian brain.