Multiomic Single-Nucleus Profiling Reveals Cell-Type-Specific Epigenetic and Transcriptional Dysregulation in Major Depressive Disorder Brain.

Authors

Aleen Francis, Yogesh Dwivedi

Published in

The international journal of neuropsychopharmacology. Aug 22, 2026. Epub Aug 22, 2026.

Abstract

Major Depressive Disorder (MDD) is a leading global cause of disability, marked by persistent mood disturbances, cognitive deficits, and changes in prefrontal cortex neural circuitry. In this study, we aimed to define cell-type-specific molecular and regulatory mechanisms underlying MDD by mapping gene-expression and chromatin-accessibility changes in the dorsolateral PFC (dlPFC).
Postmortem dlPFC (BA9) tissue from 7 MDD and 8 well-matched controls was analyzed using 10x Genomics snRNA-seq and paired ATAC+RNA multiome sequencing. Sequencing data were processed with Cell Ranger pipelines, nuclei were filtered for quality and doublets/debris, and datasets were integrated and clustered using Seurat/Signac packages. Differential gene expression, chromatin accessibility, and transcription factor motif activity were tested between MDD and controls within each cell type, followed by peak-to-gene linkage and GO/KEGG and PsyGeNET enrichment to interpret dysregulated regulatory mechanisms.
A total of 20 distinct clusters encompassing major neuronal and non-neuronal populations were identified. Differential analyses uncovered extensive cell type-specific changes in chromatin accessibility and gene expression, particularly within excitatory layer 5/6 and inhibitory Pvalb neurons, as well as glial and vascular populations. Functional enrichment indicated dysregulation of synaptic organization, neurotransmission, myelination, stress-response, and immune-regulatory pathways across neuronal and non-neuronal cells. Notably, glucocorticoid-responsive transcription factors NR3C1/NR3C2 exhibited conserved regulatory networks implicating stress signaling in MDD pathophysiology.
Together, these findings provide a comprehensive single-nucleus atlas of gene regulation in the MDD PFC, highlighting coordinated dysfunction across neurons, glia, and vascular cells.

PMID:
42630054
Bibliographic data and abstract were imported from PubMed on 22 Aug 2026.

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