A multi-regional human brain atlas of chromatin accessibility and gene expression facilitates promoter-isoform resolution genetic fine-mapping
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 prof...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54448-y |
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| author | 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 Panos Roussos |
| author_facet | 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 Panos Roussos |
| author_sort | Pengfei Dong |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d686ee4f494c4e079b4e07921e0b1530 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-d686ee4f494c4e079b4e07921e0b15302024-11-24T12:33:24ZengNature PortfolioNature Communications2041-17232024-11-0115111810.1038/s41467-024-54448-yA multi-regional human brain atlas of chromatin accessibility and gene expression facilitates promoter-isoform resolution genetic fine-mappingPengfei Dong0Liting Song1Jaroslav Bendl2Ruth Misir3Zhiping Shao4Jonathan Edelstien5David A. Davis6Vahram Haroutunian7William K. Scott8Susanne Acker9Nathan Lawless10Gabriel E. Hoffman11John F. Fullard12Panos Roussos13Center for Disease Neurogenomics, Icahn School of Medicine at Mount SinaiCenter for Disease Neurogenomics, Icahn School of Medicine at Mount SinaiCenter for Disease Neurogenomics, Icahn School of Medicine at Mount SinaiFriedman Brain Institute, Icahn School of Medicine at Mount SinaiCenter for Disease Neurogenomics, Icahn School of Medicine at Mount SinaiFriedman Brain Institute, Icahn School of Medicine at Mount SinaiBrain Endowment Bank, Department of Neurology, Miller School of Medicine, University of MiamiFriedman Brain Institute, Icahn School of Medicine at Mount SinaiBrain Endowment Bank, Department of Neurology, Miller School of Medicine, University of MiamiGlobal Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH and Co. KGGlobal Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH and Co. KGCenter for Disease Neurogenomics, Icahn School of Medicine at Mount SinaiCenter for Disease Neurogenomics, Icahn School of Medicine at Mount SinaiCenter for Disease Neurogenomics, Icahn School of Medicine at Mount SinaiAbstract 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.https://doi.org/10.1038/s41467-024-54448-y |
| spellingShingle | 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 Panos Roussos A multi-regional human brain atlas of chromatin accessibility and gene expression facilitates promoter-isoform resolution genetic fine-mapping Nature Communications |
| title | A multi-regional human brain atlas of chromatin accessibility and gene expression facilitates promoter-isoform resolution genetic fine-mapping |
| title_full | A multi-regional human brain atlas of chromatin accessibility and gene expression facilitates promoter-isoform resolution genetic fine-mapping |
| title_fullStr | A multi-regional human brain atlas of chromatin accessibility and gene expression facilitates promoter-isoform resolution genetic fine-mapping |
| title_full_unstemmed | A multi-regional human brain atlas of chromatin accessibility and gene expression facilitates promoter-isoform resolution genetic fine-mapping |
| title_short | A multi-regional human brain atlas of chromatin accessibility and gene expression facilitates promoter-isoform resolution genetic fine-mapping |
| title_sort | multi regional human brain atlas of chromatin accessibility and gene expression facilitates promoter isoform resolution genetic fine mapping |
| url | https://doi.org/10.1038/s41467-024-54448-y |
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