A multi-regional human brain atlas of chromatin accessibility and gene expression facilitates promoter-isoform resolution genetic fine-mapping
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.
Authors
- Nathan Lawless (ORCID: https://orcid.org/0000-0002-3120-1126)
- John F. Fullard (ORCID: https://orcid.org/0000-0001-9874-2907)
- Zhiping Shao (ORCID: https://orcid.org/0009-0006-4889-6637)
- Susanne Acker
- Pengfei Dong (ORCID: https://orcid.org/0000-0003-3735-5158)
- Gabriel E. Hoffman (ORCID: https://orcid.org/0000-0002-0957-0224)
- Jaroslav M. Bendl (ORCID: https://orcid.org/0000-0001-9989-2720)
- Vahram H. Haroutunian (ORCID: https://orcid.org/0000-0001-5860-2512)
- Ruth Misir
- Panos Roussos (ORCID: https://orcid.org/0000-0002-4640-6239)
- Liting Song (ORCID: https://orcid.org/0000-0003-2261-0689)
- Jonathan Edelstien
- David A. Davis (ORCID: https://orcid.org/0000-0002-9323-6180)
- William K. Scott (ORCID: https://orcid.org/0000-0001-9336-6404)
Institutions
- Allen Institute for Brain Science (US)
- Boehringer Ingelheim (Germany) (DE)
- University of Miami (US)
- James J. Peters VA Medical Center (US)
- Mental Illness Research, Education and Clinical Centers (US)
- Translational Therapeutics (United States) (US)
- Dr. John T. Macdonald Foundation (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-21
- DOI
- https://doi.org/10.1038/s41467-024-54448-y
- Citations
- 4
- Primary Topic
- Genomics and Chromatin Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 0.94
Funders
- Brain and Behavior Research Foundation
- Alzheimer's Association
- University of Miami
- Icahn School of Medicine at Mount Sinai
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health
- Leonard M. Miller School of Medicine
- Leonard M. Miller School of Medicine, University of Miami
- National Institute on Aging
- National Institute of Mental Health
- NIH Clinical Center