Sex-divergent microRNA–mRNA regulatory networks in the dorsolateral prefrontal cortex in major depressive disorder

Abstract Post-mortem studies have identified transcriptomic alterations in major depressive disorder (MDD), but sex-specific post-transcriptional mechanisms remain poorly understood. Here, we profiled microRNAs and mRNAs in the dorsolateral prefrontal cortex of males and females with MDD, most of whom died by suicide, and sex-matched controls. We integrated these profiles with experimentally supported microRNA–target interactions, validated selected changes by RT-qPCR, and mapped targets using an independent single-nucleus transcriptomic dataset. Differentially expressed microRNAs were predominantly upregulated in males and downregulated in females (73% in each sex), and differentially expressed genes largely differed between sexes; most shared microRNAs and genes altered in both sexes changed in opposite directions. In males, microRNA-mRNA regulatory networks involved genes related to proteostasis and intracellular trafficking, and mapped mainly to excitatory neurons. In females, these networks involved genes related to metabolism and neuroendocrine-immune signaling, distributed across neuronal, glial, and vascular cells. These findings reveal sex-divergent post-transcriptional regulation in MDD and support sex-stratified biomarker and therapeutic research.

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Publication Details

Journal
Research Square
Published
2026-11-02
DOI
https://doi.org/10.21203/rs.3.rs-11555499/v1
Primary Topic
Treatment of Major Depression
Type
preprint
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preprint

Sex-divergent microRNA–mRNA regulatory networks in the dorsolateral prefrontal cortex in major depressive disorder

Gustavo Turecki, J. Javier Meana, Marı́a J. Portella, Lluís Miquel-Rio et al.
2 links
Research Square
Treatment of Major Depression
preprint

Sex-divergent microRNA–mRNA regulatory networks in the dorsolateral prefrontal cortex in major depressive disorder

Gustavo Turecki, J. Javier Meana, Marı́a J. Portella, Lluís Miquel-Rio, Javier de Diego-Adeliño, Muriel Vicent-Gil, Eduard Vieta, Analı́a A Bortolozzi, Luis Felipe Callado, Cristina Fornaguera, Esther Ruiz‐Bronchal, Judith Jericó-Escolar, Veónica Paz
preprint en

Abstract

Abstract Post-mortem studies have identified transcriptomic alterations in major depressive disorder (MDD), but sex-specific post-transcriptional mechanisms remain poorly understood. Here, we profiled microRNAs and mRNAs in the dorsolateral prefrontal cortex of males and females with MDD, most of whom died by suicide, and sex-matched controls. We integrated these profiles with experimentally supported microRNA–target interactions, validated selected changes by RT-qPCR, and mapped targets using an independent single-nucleus transcriptomic dataset. Differentially expressed microRNAs were predominantly upregulated in males and downregulated in females (73% in each sex), and differentially expressed genes largely differed between sexes; most shared microRNAs and genes altered in both sexes changed in opposite directions. In males, microRNA-mRNA regulatory networks involved genes related to proteostasis and intracellular trafficking, and mapped mainly to excitatory neurons. In females, these networks involved genes related to metabolism and neuroendocrine-immune signaling, distributed across neuronal, glial, and vascular cells. These findings reveal sex-divergent post-transcriptional regulation in MDD and support sex-stratified biomarker and therapeutic research.

Research Square
Consejo Superior de Investigaciones Científicas (ES), University of the Basque Country (ES), Instituto de Salud Carlos III (ES), Hospital de Sant Pau (ES), Centro de Investigación Biomédica en Red de Salud Mental (ES), Institut d'Investigacions Biomèdiques de Barcelona (ES), Institut Químic de Sarrià (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Institut de Recerca Sant Pau (ES), McGill University (CA), Universitat Ramon Llull (ES), Universitat de Barcelona (ES)
Good health and well-being
Treatment of Major Depression
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