Program in Bioinformatics and Integrative Biology; Department of Biochemistry and Molecular Pharmacology; Graduate School of Biomedical Sciences
Cell Biology | Developmental Neuroscience | Molecular and Cellular Neuroscience | Nervous System Diseases | Neurology | Psychiatry | Psychiatry and Psychology
Cellular heterogeneity in the human brain obscures the identification of robust cellular regulatory networks, which is necessary to understand the function of non-coding elements and the impact of non-coding genetic variation. Here we integrate genome-wide chromosome conformation data from purified neurons and glia with transcriptomic and enhancer profiles, to characterize the gene regulatory landscape of two major cell classes in the human brain. We then leverage cell-type-specific regulatory landscapes to gain insight into the cellular etiology of several brain disorders. We find that Alzheimer's disease (AD)-associated epigenetic dysregulation is linked to neurons and oligodendrocytes, whereas genetic risk factors for AD highlighted microglia, suggesting that different cell types may contribute to disease risk, via different mechanisms. Moreover, integration of glutamatergic and GABAergic regulatory maps with genetic risk factors for schizophrenia (SCZ) and bipolar disorder (BD) identifies shared (parvalbumin-expressing interneurons) and distinct cellular etiologies (upper layer neurons for BD, and deeper layer projection neurons for SCZ). Collectively, these findings shed new light on cell-type-specific gene regulatory networks in brain disorders.
Epigenetics, Epigenomics, Chromatin, Epigenetics in the nervous system, Genetics of the nervous system
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DOI of Published Version
Hu B, Won H, Mah W, Park RB, Kassim B, Spiess K, Kozlenkov A, Crowley CA, Pochareddy S; PsychENCODE Consortium, Li Y, Dracheva S, Sestan N, Akbarian S, Geschwind DH. Neuronal and glial 3D chromatin architecture informs the cellular etiology of brain disorders. Nat Commun. 2021 Jun 25;12(1):3968. doi: 10.1038/s41467-021-24243-0. PMID: 34172755; PMCID: PMC8233376. Link to article on publisher's site
Hu B, Won H, Mah W, Park RB, Kassim B, Spiess K, Kozlenkov A, Crowley CA, Pochareddy S, Li Y, Dracheva S, Sestan N, Akbarian S, Geschwind DH, PsychENCODE Consortium, Mattei E, Purcaro MJ, Weng Z, Moore JE, Pratt HE, Huey J, Borrman TM. (2021). Neuronal and glial 3D chromatin architecture informs the cellular etiology of brain disorders. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1038/s41467-021-24243-0. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/2065
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
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