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

Comments

Eugenio Mattei, Michael Purcaro, Zhiping Weng, Jill Moore, Henry Pratt, Jack Huey, and Tyler Borrman are collaborators in the PsychENCODE Consortium.

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Nature communications

PubMed ID

34172755

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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