Multiomic single-nucleus profiling reveals cell-type-specific epigenetic and transcriptional dysregulation in major depressive disorder brain.

Aleena Francis; Yogesh Dwivedi

doi:10.1093/ijnp/pyag045

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Multiomic single-nucleus profiling reveals cell-type-specific epigenetic and transcriptional dysregulation in major depressive disorder brain.

Aleena Francis·Yogesh Dwivedi

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Abstract

OBJECTIVE: 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 prefrontal cortex (PFC) (dlPFC). METHODS: Postmortem dlPFC (BA9) tissue from 7 MDD and 8 well-matched controls was analyzed using 10× 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 Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and PsyGeNET enrichment to interpret dysregulated regulatory mechanisms. RESULTS: 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. CONCLUSIONS: 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.

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Major Depressive Disorder Humans Epigenesis, Genetic Multiomics Dorsolateral Prefrontal Cortex Male Female Receptors, Glucocorticoid Gene Expression Regulation Neurons Prefrontal Cortex ATAC-seq chromatin depression dorsolateral prefrontal cortex single-nucleus transcriptome Journal Article

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Aleena Francis, Yogesh Dwivedi. 2026-09-01. Multiomic single-nucleus profiling reveals cell-type-specific epigenetic and transcriptional dysregulation in major depressive disorder brain.. https://doi.org/10.1093/ijnp%2Fpyag045

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