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

Pengfei Dong (), Liting Song, Jaroslav Bendl, Ruth Misir, Zhiping Shao, Jonathan Edelstien, David A. Davis, Vahram Haroutunian, William K. Scott, Susanne Acker, Nathan Lawless, Gabriel E. Hoffman, John F. Fullard and Panos Roussos ()
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Pengfei Dong: Icahn School of Medicine at Mount Sinai
Liting Song: Icahn School of Medicine at Mount Sinai
Jaroslav Bendl: Icahn School of Medicine at Mount Sinai
Ruth Misir: Icahn School of Medicine at Mount Sinai
Zhiping Shao: Icahn School of Medicine at Mount Sinai
Jonathan Edelstien: Icahn School of Medicine at Mount Sinai
David A. Davis: University of Miami
Vahram Haroutunian: Icahn School of Medicine at Mount Sinai
William K. Scott: University of Miami
Susanne Acker: Boehringer Ingelheim Pharma GmbH and Co. KG
Nathan Lawless: Boehringer Ingelheim Pharma GmbH and Co. KG
Gabriel E. Hoffman: Icahn School of Medicine at Mount Sinai
John F. Fullard: Icahn School of Medicine at Mount Sinai
Panos Roussos: Icahn School of Medicine at Mount Sinai

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54448-y

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