Stress Rewires Brain Genes via RNA Switches: UAB Research Shows How Stress Alters Brain Gene Activity

UAB Researchers Uncover How Stress Hormones Flip RNA Switches to Silence Brain Genes

A groundbreaking study from the University of Alabama at Birmingham (UAB) has illuminated a previously unknown mechanism by which stress rewires brain genes. Researchers in the Department of Psychiatry and Behavioral Neurobiology at UAB's Heersink School of Medicine discovered that stress hormones activate long noncoding RNAs (lncRNAs)—molecules that do not code for proteins but regulate gene expression—as "switches" to turn off thousands of essential neuronal genes. 69 70

Long noncoding RNAs, often abbreviated as lncRNAs, are a class of RNA molecules longer than 200 nucleotides that play crucial roles in epigenetic regulation, the process where gene activity is modified without changing the DNA sequence itself. In this research, published in the journal Genomic Psychiatry, the team led by Distinguished Professor Yogesh Dwivedi, Ph.D., demonstrated how chronic stress exposure leads to lasting changes in brain cell communication, potentially contributing to disorders like depression and post-traumatic stress disorder (PTSD).

The study utilized an innovative in vitro model using SH-SY5Y neuronal cells overexpressing the NR3C1 gene, which encodes the glucocorticoid receptor (GR). This receptor is the primary mediator of stress responses in the body, activated by hormones like cortisol in humans or corticosterone in rodents. By mimicking prolonged GR activation, the model simulated the dysregulated hypothalamic-pituitary-adrenal (HPA) axis seen in chronic stress conditions.

This discovery positions UAB at the forefront of neuroepigenetics research, a field exploring how environmental factors like stress influence gene expression in the brain. With UAB consistently ranked among the top institutions for neuroscience and psychiatry—placing in the top 130 globally for neuroscience and behavior by U.S. News & World Report—the university continues to attract top talent and federal funding from the National Institute of Mental Health (NIMH). 122

The Step-by-Step Mechanism: From Stress Signal to Gene Silencing

Understanding the process requires breaking down the molecular cascade. First, stress triggers the release of glucocorticoid hormones, which bind to and activate the glucocorticoid receptor (GR) in brain cells. Once activated, GR translocates to the nucleus, where it influences transcription.

Step 1: GR activation leads to the upregulation of specific lncRNAs. The UAB study identified 79 such lncRNAs significantly altered (44 upregulated, 35 downregulated; p < 0.05), with six emerging as hub regulators based on network analysis. 70

• These lncRNAs act as guides, tethering the polycomb repressive complex 2 (PRC2)—a key epigenetic silencer—to target chromatin regions.
• PRC2's catalytic subunit, EZH2, deposits repressive histone marks like H3K27me3, compacting chromatin and blocking gene access.
• Result: Over 3,000 genes involved in synaptic vesicle transport, neurotransmitter signaling (e.g., serotonin, dopamine pathways), calcium signaling, and neuroplasticity are silenced.

RNA immunoprecipitation sequencing (RIP-seq) confirmed 89 lncRNAs enriched in EZH2 and 57 in H3K27me3, with inverse correlations between lncRNA levels and nearby gene expression (R = –0.21, p < 0.005). 70 This creates an "epigenetic echo," where transient stress imprints permanent changes, explaining why chronic stress persists even after the stressor resolves.

In practical terms, silenced genes disrupt TrkA/TrkB signaling, PI3K-AKT pathways, and glycosylphosphatidylinositol-anchor biosynthesis— all implicated in mood regulation and neuronal resilience.

Key Findings: 79 lncRNAs and 3,000 Silenced Genes

The UAB team's RNA sequencing revealed profound impacts. Volcano plots and chromosomal circos diagrams highlighted lncRNA dysregulation across the genome. Functional enrichment analysis pinpointed calcium signaling (p < 0.01) and 33 Reactome pathways affected.

Hub lncRNAs like ENSG00000225963.8 were upregulated under GR stress and bound PRC2 strongly. These findings build on prior work linking lncRNAs to PTSD resilience and depression phenotypes. 91 96

Statistics underscore the scale: Chronic stress affects an estimated 70% of U.S. adults yearly per APA's Stress in America 2025 report, with PTSD prevalence at 3.6-5% (higher in women at 5.2%) and major depressive disorder at 15.5%. 112 120

Implications for Mental Health Disorders in the U.S.

This mechanism explains the persistence of stress-related conditions. In PTSD, affecting 13 million Americans annually, silenced neuroplasticity genes hinder recovery. Similarly, in depression, disrupted neurotransmitter pathways align with symptom profiles.

UAB's Depression and Suicide Center, co-directed by Dwivedi, leverages this for precision medicine. Dwivedi notes, "Specific lncRNAs could become biomarkers for stress vulnerability or targets for next-generation antidepressants aimed at restoring chromatin flexibility." 69

Broader impacts include neurodegenerative links, as chromatin rigidity mirrors Alzheimer's patterns. For higher education, this fuels demand for neuroepigenetics expertise in university labs nationwide.

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UAB's Leadership in Psychiatry and Neuroscience Research

Yogesh Dwivedi, with over 219 publications and 12,325 citations, leads NIMH-funded projects (e.g., R01MH130539). Postdocs like Anuj K. Verma and Bhaskar Roy exemplify UAB's training pipeline. 90

UAB ranks #52 in U.S. psychology and top 130 globally in neuroscience, supported by the Alabama Brain Collection for postmortem studies. 128 Explore research jobs or professor positions in similar fields at leading universities.

From Bench to Bedside: Emerging Therapies and Solutions

Targeting lncRNA-PRC2 interactions could reverse silencing. CRISPR-based editing or small molecules disrupting EZH2-lncRNA binding show promise in preclinical models. Circulating lncRNAs as blood biomarkers enable non-invasive stress monitoring.

• Potential for personalized antidepressants acting faster than SSRIs.
• Early intervention in high-risk groups like veterans or first responders.
• Integration with cognitive behavioral therapy to enhance neuroplasticity.

Related studies confirm lncRNAs in PTSD susceptibility (e.g., hippocampal changes post-trauma). 91

Stakeholder Perspectives: Researchers, Clinicians, and Policymakers

Dwivedi emphasizes precision medicine potential. Editorialists Julio Licinio and Ma-Li Wong highlight the GR-lncRNA-PRC2 axis as a psychiatric biology frontier. Clinicians see biomarker utility for treatment-resistant depression.

In higher ed, this spurs interdisciplinary programs in epigenomics. UAB's grants model successful funding strategies for aspiring PIs.

Challenges and Future Outlook in Neuroepigenetics

Limitations include cellular model validation in vivo and human brains. Future: Brain organoids from patient iPSCs, longitudinal studies tracking lncRNA changes.

By 2030, lncRNA therapies could transform mental health, reducing U.S. economic burden ($210B/year for depression). Universities like UAB will lead. 120

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Career Opportunities in Stress and Brain Research

This UAB breakthrough highlights booming demand for neuroepigenetics experts. Postdoc positions in labs studying lncRNAs abound, leading to faculty roles. Check postdoc jobs or career advice.

Rate professors in neuroscience via Rate My Professor for insights into top programs.

Conclusion: Rewiring Resilience Through Research

UAB's RNA switches discovery offers hope against stress's brain toll. Explore Rate My Professor, Higher Ed Jobs, Career Advice, University Jobs, or post a job to join this revolution. For more, visit higher ed policy impacts.