Neuronal and glial 3D chromatin architecture informs the cellular etiology of brain disorders.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • June 25, 2021

Published In

Volume / Issue

  • 12 / 1

Start / End Page

  • 3968 -

PubMed ID

  • 34172755

Pubmed Central ID

  • PMC8233376

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/s41467-021-24243-0

Language

  • eng

Conference Location

  • England