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A multi-regional human brain atlas of chromatin accessibility and gene expression facilitates promoter-isoform resolution genetic fine-mapping.

39578476
PMC11584674
Nature communications
Nov. 22, 2024
Center for Precision Medicine and Translational Therapeutics, James J. Peters VA Medical Center, Bronx, NY, USA. panagiotis.roussos@mssm.edu.
Enhancer Elements, Genetic, Chromatin, Promoter Regions, Genetic, Protein Isoforms, Gene Expression Regulation, Brain, Transcriptome, Adult, Male, Female, Humans, Atlases as Topic
R01 MH125246, U01 MH116442, R01 AG067025, R01 AG065582, R01 AG050986, R01 MH109677, R01-AG050986, R01-AG065582, AARF-21-722200, 26313, R01-MH125246, R01-AG067025, RF1 MH128970, 29683, RF1-MH128970, U01-MH116442
Shao Z, Haroutunian V, Fullard JF, Roussos P, Song L, Davis DA, Dong P, Hoffman GE, Bendl J, Misir R, Scott WK, Acker S, Edelstien J, Lawless N
Dong P, Song L, Bendl J, Misir R, Shao Z, Edelstien J, Davis DA, Haroutunian V, Scott WK, Acker S, Lawless N, Hoffman GE, Fullard JF, Roussos P. A multi-regional human brain atlas of chromatin accessibility and gene expression facilitates promoter-isoform resolution genetic fine-mapping. Nature communications. 2024 Nov 22.

Abstract

Brain region- and cell-specific transcriptomic and epigenomic features are associated with heritability for neuropsychiatric traits, but a systematic view, considering cortical and subcortical regions, is lacking. Here, we provide an atlas of chromatin accessibility and gene expression profiles in neuronal and non-neuronal nuclei across 25 distinct human cortical and subcortical brain regions from 6 neurotypical controls. We identified extensive gene expression and chromatin accessibility differences across brain regions, including variation in alternative promoter-isoform usage and enhancer-promoter interactions. Genes with distinct promoter-isoform usage across brain regions were strongly enriched for neuropsychiatric disease risk variants. Moreover, we built enhancer-promoter interactions at promoter-isoform resolution across different brain regions and highlighted the contribution of brain region-specific and promoter-isoform-specific regulation to neuropsychiatric disorders. Including promoter-isoform resolution uncovers additional distal elements implicated in the heritability of diseases, thereby increasing the power to fine-map risk genes. Our results provide a valuable resource for studying molecular regulation across multiple regions of the human brain and underscore the importance of considering isoform information in gene regulation.