Stress hormones may silence crucial neuronal genes through specific RNA molecules

What if the brain's response to stress could be read not in fleeting neurotransmitter bursts, but in the quieting of genes deep inside chromatin? Researchers at the University of Alabama at Birmingham have now shown that stress hormones may silence crucial neuronal genes through an unexpected class of RNA molecules that operate not by encoding proteins, but by reshaping the genome's architecture.

Stress, the genome, and a hidden layer of regulation.

The study, led by Professor Yogesh Dwivedi, Distinguished Professor and Elesabeth Ridgely Shook Endowed Chair in the Department of Psychiatry and Behavioral Neurobiology, uncovers how long noncoding RNAs (lncRNAs) associate with the polycomb repressive complex 2 (PRC2) to modify chromatin following activation of the glucocorticoid receptor (GR)-the cell's master regulator of stress response.

In the words of Professor Dwivedi:

"Our results point to a structural route by which stress hormones influence gene expression. We observed that specific lncRNAs partner with polycomb proteins to silence nearby genes, including many linked to synaptic function. This is not just transcriptional noise-it is the architecture of stress itself."

The scientific challenge

Stress is both adaptive and destructive. When brief, it sharpens focus and mobilizes energy. When prolonged, it rewires the brain, eroding resilience and contributing to disorders such as major depressive disorder (MDD). While decades of research have documented how stress hormones activate the hypothalamic-pituitary-adrenal (HPA) axis, scientists have struggled to pinpoint how those transient signals leave enduring molecular marks.

Epigenetics-heritable changes in gene activity without DNA sequence alteration-has emerged as a prime suspect. In particular, the glucocorticoid receptor, which mediates the effects of cortisol, is known to enter the nucleus and influence transcription. Yet exactly how GR activation produces durable repression of neuronal genes remained an open question.

Could lncRNAs be the missing intermediaries? These enigmatic molecules do not code for proteins but bind to chromatin-modifying complexes, effectively guiding where and when the genome is opened or closed.

A mechanistic experiment in miniature

To investigate, the Dwivedi team constructed a controlled model of sustained stress signaling. Using SH-SY5Y neuronal cells, they overexpressed the glucocorticoid receptor gene (NR3C1), achieving continuous GR activation without the pharmacological variability of hormone stimulation. This setup mimicked the chronic, dysregulated HPA axis activity characteristic of stress-related disorders.

The researchers then performed strand-specific RNA sequencing (RNA-seq) to map the expression of more than 12,000 lncRNAs. Under GR activation, 79 lncRNAs were significantly altered (44 upregulated, 35 downregulated; p < 0.05). Several of these appeared on chromosomes 11 and 12, regions previously associated with stress-linked transcriptional changes.

Next came a critical test: could these RNAs interact with chromatin-silencing machinery? Through RNA immunoprecipitation sequencing (RIP-seq) using antibodies against EZH2, the catalytic subunit of PRC2, and H3K27me3, a repressive histone mark, the team found that 89 lncRNAs were enriched in the EZH2-bound fraction and 57 in the H3K27me3 fraction.

"These RNAs seem to act like postal codes for gene repression," said Dr. Anuj K. Verma, lead author of the study. "They help direct the polycomb complex to precise chromatin neighborhoods where stress-induced silencing occurs."

The dual enrichment strongly supports a model in which GR-induced lncRNAs recruit PRC2 to target loci, prompting histone methylation and local gene shutdown.

From molecular silence to synaptic consequence

When the team compared lncRNA and mRNA datasets, the correlations were striking. Genome-wide, lncRNA levels inversely tracked with transcription of nearby genes (R = –0.21, p < 0.005). Within repressed chromatin domains, this relationship strengthened (r = –0.071 and –0.037, p < 0.0001) for lncRNAs bound to EZH2 and H3K27me3, respectively.

Downregulated genes clustered around synaptic vesicle transport, neurotransmitter receptor regulation, and calcium signaling-the same processes disrupted in depression and chronic stress. Functional enrichment analyses identified calcium signaling (p < 0.01) and glycosylphosphatidylinositol-anchor biosynthesis (p < 0.05) as top affected pathways, with Reactome mapping revealing 33 altered cascades, including TrkA/TrkB, FGFR, and PI3K-AKT pathways.

These signaling axes regulate neuronal excitability and dendritic spine integrity-features compromised in MDD. "What emerges is an epigenetic echo of stress," said Dr. Bhaskar Roy, study coauthor. "The brain's stress machinery does not merely toggle genes on and off; it reconfigures the chromatin landscape that decides which genes can speak."

Understanding the science

To visualize the findings, the authors provide heatmaps, volcano plots, and chromosomal "circos" diagrams illustrating the distribution of up- and downregulated lncRNAs. A network analysis revealed six hub lncRNAs acting as major nodes in the stress-induced transcriptional network. Among these, three stood out-ENSG00000225963.8, ENSG00000228412.9, and ENSG00000254211.6-each upregulated under GR activation and enriched in both EZH2 and H3K27me3 complexes.

These RNAs may act as key scaffolds that tether PRC2 to stress-responsive loci. Analogously, one could think of them as molecular bookmarks inserted into the genome during stress, marking which pages to keep closed long after the initial stimulus has passed.

From discovery to impact

The potential implications stretch far beyond the petri dish. Stress-induced changes in chromatin structure have been implicated in a range of psychiatric and neurodegenerative conditions. If specific lncRNAs mediate these changes, they could become biomarkers for stress vulnerability or targets for next-generation antidepressants aimed at restoring chromatin flexibility.

Current antidepressants modulate neurotransmitters such as serotonin or norepinephrine, but their delayed onset suggests deeper molecular inertia. By identifying non-coding RNAs that physically guide chromatin repression, this study hints at an epigenetic layer of control that drugs might one day reverse.

Could interventions that modulate lncRNA–PRC2 interaction reawaken silenced genes involved in neuroplasticity? Could circulating RNA fragments reflect an individual's stress load? Such questions could reshape how psychiatry conceptualizes resilience-not merely as coping behavior, but as molecular adaptability.

"If we can identify individuals whose lncRNA profiles predict maladaptive chromatin responses to stress, we may be able to intervene earlier," Professor Dwivedi noted. "That vision remains in the future, but this study provides the mechanistic groundwork."

The team behind the discovery

All authors are affiliated with the Heersink School of Medicine, University of Alabama at Birmingham. The project was supported by multiple grants from the U.S. National Institute of Mental Health (R01MH130539, R01MH124248, R01MH118884, R01MH128994, R01MH107183, and R56MH138596). The multidisciplinary team integrated expertise in psychiatry, neurobiology, and computational genomics.

Limitations and caveats

The researchers acknowledge that these results derive from a cellular model and should not be generalized to the human brain without additional validation. The correlations reported are statistical associations, not causal demonstrations. Confidence intervals were not specified in the source manuscript, though p values were provided. Functional tests-such as silencing or overexpressing the identified lncRNAs in neurons-will be essential to determine causality.

Still, the study's integration of transcriptomic, epigenomic, and genome-wide chromatin-level data provides one of the clearest mechanistic links yet between glucocorticoid signaling and durable transcriptional repression.

The road ahead

Future directions naturally follow from the data.

• Can these lncRNAs serve as blood-detectable biomarkers of chronic stress exposure?
• How do they behave in brain organoids derived from patients with depression?
• Could pharmacological disruption of PRC2-lncRNA binding reverse pathological silencing?
• Might early-life stress leave durable RNA "signatures" in chromatin that predispose to later illness?
• And, fundamentally, can manipulating these molecular mediators enhance stress resilience?

Answering such questions could reframe the search for antidepressants, focusing not only on synapses but also on the chromatin code that governs them.

Broader context

In the broader landscape of psychiatric research, the work exemplifies how basic molecular biology can illuminate the persistent shadow of stress. The discovery of a GR–lncRNA–PRC2 axis bridges two fields-endocrinology and epigenomics-that historically evolved apart. It also underscores that mental health disorders are as much disorders of information storage as of emotion or behavior.

By integrating molecular precision with translational relevance, this study represents a step toward understanding how stress reshapes not only how we feel but how our genome remembers.

Concluding statement

This peer-reviewed research represents a significant advance in neuroepigenomics, offering new insights into chromatin-associated lncRNA activity through rigorous experimental investigation. The findings provide critical evidence for understanding stress-linked transcriptional regulation via a GR-lncRNA-PRC2 axis. By employing an integrative transcriptomic and RIP-seq approach, the research team has generated data that not only advances fundamental knowledge but also suggests practical applications in biomarker discovery and mechanistic target identification. The reproducibility and validation of these findings through the peer-review process ensures their reliability and positions them as a foundation for future investigations. This work exemplifies how cutting-edge research can bridge the gap between basic science and translational applications, potentially impacting patients, clinicians, and researchers in the coming years.

This groundbreaking peer-reviewed research has been selected as the cover article for Genomic Psychiatry, reflecting its significance to the field of psychiatric genomics. The study is accompanied by an editorial authored by Drs. Julio Licinio and Ma-Li Wong, who contextualize these findings within the broader landscape of stress biology and psychiatric research. The editorial highlights how this work illuminates critical mechanisms linking environmental stress to persistent changes in gene expression patterns through lncRNA-mediated chromatin modifications.

The comprehensive nature of this investigation, spanning multiple RNA sequencing modalities and network analyses, provides insights that will reshape how the field approaches lncRNA-mediated chromatin regulation in stress contexts. Furthermore, the interdisciplinary collaboration between molecular psychiatry and chromatin biology demonstrates the power of combining diverse expertise to tackle complex scientific questions.