University of Massachusetts Medical School Faculty Publications
UMMS Affiliation
Program in Bioinformatics and Integrative Biology; Department of Biochemistry and Molecular Pharmacology; Graduate School of Biomedical Sciences
Publication Date
2021-06-25
Document Type
Article
Disciplines
Cell Biology | Developmental Neuroscience | Molecular and Cellular Neuroscience | Nervous System Diseases | Neurology | Psychiatry | Psychiatry and Psychology
Abstract
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.
Keywords
Epigenetics, Epigenomics, Chromatin, Epigenetics in the nervous system, Genetics of the nervous system
Rights and Permissions
Copyright © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
DOI of Published Version
10.1038/s41467-021-24243-0
Source
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
Related Resources
Journal/Book/Conference Title
Nature communications
PubMed ID
34172755
Repository Citation
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.
Included in
Cell Biology Commons, Developmental Neuroscience Commons, Molecular and Cellular Neuroscience Commons, Nervous System Diseases Commons, Neurology Commons, Psychiatry Commons, Psychiatry and Psychology Commons
Comments
Eugenio Mattei, Michael Purcaro, Zhiping Weng, Jill Moore, Henry Pratt, Jack Huey, and Tyler Borrman are collaborators in the PsychENCODE Consortium.