The majority of disease-associated genetic variation resides in non-coding regions of the genome, which holds true for neurological and psychiatric disorders; many disease-causing variants exert their effects by affecting gene expression regulation. A new study in Science has mapped regulatory elements for major cell types of the human brain to help elucidate the transcriptional mechanisms underlying their developmental and functional properties in health and disease.

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Using fluorescence-activated nuclei sorting, Nott et al. isolated astrocyte, microglial, neuronal and oligodendrocyte nuclei from resected cortical brain tissue of six different individuals and performed assay for transposase-accessible chromatin sequencing (ATAC-seq) to identify open chromatin regions in 200,000 cell type-specific nuclei. Moreover, 500,000 nuclei were analysed by chromatin immunoprecipitation followed by sequencing (ChIP–seq) for the histone 3 marks lysine 27 acetylation (H3K27ac) and lysine 4 trimethylation (H3K4me3) to pinpoint active enhancers and promoters, respectively, in each cell type. The authors found a “one-to-many relationship between promoters and enhancers”, as previously identified. In contrast to active promoters, most of which were shared across cell types, the fraction of active enhancers that overlapped between different cell types was fairly small. This finding is indicative of cell-type specificity being modulated predominantly by the enhancer repertoire.

Linkage disequilibrium score regression was applied to genome-wide association study (GWAS) summary statistics to estimate single-nucleotide polymorphism-based heritabilities, identifying an association between neuron-specific variants in transcriptional enhancers or promoters and psychiatric disorders or behavioural traits. By contrast, Alzheimer disease risk variants were found to be most prominent in microglia-specific enhancers.

Proximity ligation-assisted ChIP–seq (PLAC-seq), in which active promoters are enriched by H3K4me3 ChIP–seq after a proximity ligation step, mapped chromatin loops between active promoters and distal regulatory regions in microglia, neurons and oligodendrocytes, leading to the identification of 219,509 significant interactions across cell types. This interactome information was able to support the interpretation of disease risk variants threefold: by linking risk variants to more distal active promoters; by extending the identification of genes linked to enhancers harbouring risk variants beyond genes known from GWAS; and by identifying cell type-specific enhancers harbouring risk variants linked to genes expressed in multiple cell types, suggestive of cell type-specific disease susceptibility.

These brain cell type-specific enhancer–promoter interactome maps will serve as a useful resource to identify genes that influence neurological and psychiatric disorders and the cell types in which they function.