In a groundbreaking advance that could profoundly alter our understanding of stress biology and psychiatric disorders, researchers at the University of Alabama at Birmingham have unveiled a molecular mechanism by which stress hormones reshape the genomic landscape. Their findings reveal that stress does not merely trigger transient bursts of neurotransmitter activity but imprints lasting silencing marks on critical neuronal genes through a sophisticated interplay involving long noncoding RNAs (lncRNAs) and chromatin-modifying complexes.

Long noncoding RNAs, enigmatic strands of RNA that do not encode proteins yet perform intricate regulatory roles, emerge as pivotal players in this process. The research team, led by Professor Yogesh Dwivedi, demonstrated that specific lncRNAs operate as molecular brokers, guiding the polycomb repressive complex 2 (PRC2) to precise locations on chromatin, thereby inducing gene silencing in response to glucocorticoid receptor (GR) activation. This receptor, the master regulator of the cellular stress response, couples external hormonal cues with alterations deep within the chromatin architecture.

A fundamental challenge in stress research has been deciphering how ephemeral hormonal signals translate into enduring changes in gene expression that fuel disorders such as major depressive disorder (MDD). While activation of the hypothalamic-pituitary-adrenal (HPA) axis and glucocorticoid receptor function are well characterized, the unexpected role of lncRNAs in channeling these signals into chromatin remodeling marks a revolutionary shift. It suggests a structural mode of gene regulation mediated not through DNA sequence changes but through epigenetic modification and spatial reconfiguration of the genome.

To interrogate these mechanisms, the researchers engineered an elegant cellular model using SH-SY5Y neuronal cells genetically modified to overexpress NR3C1, the gene encoding the glucocorticoid receptor. This setup mimics chronic, sustained stress signaling by maintaining active GR levels independent of fluctuating hormone concentrations, allowing for a robust, controlled exploration of downstream genomic effects without pharmacological confounders.

Comprehensive strand-specific RNA sequencing illuminated striking changes in the lncRNA landscape following GR overexpression. Among over 12,000 lncRNAs surveyed, 79 exhibited significant regulation, with 44 showing increased expression and 35 decreased. Notably, many regulated lncRNAs clustered on chromosomes 11 and 12, regions previously implicated in stress-related transcriptional repression, highlighting potential hotspots for chromatin remodeling induced by chronic stress.

Crucially, RNA immunoprecipitation sequencing (RIP-seq) analyses uncovered that a distinct subset of these lncRNAs physically associates with key chromatin silencing components—EZH2, the enzymatic core of PRC2, and H3K27me3, a hallmark repressive histone modification. This finding not only establishes a direct link between lncRNAs and polycomb-mediated chromatin silencing but also suggests these RNAs function as precision guides, acting akin to molecular zip codes that specify the genomic locales where stress-induced gene repression occurs.

Integrative analyses correlating lncRNA and mRNA expression patterns revealed a genome-wide inverse relationship: elevated lncRNA levels corresponded with the downregulation of adjacent genes, particularly within repressive chromatin domains enriched for EZH2 and H3K27me3 marks. Functionally, the suppressed genes are heavily involved in essential neuronal processes, including synaptic vesicle transport, neurotransmitter receptor regulation, and calcium signaling—pathways severely disrupted in depression and chronic stress conditions.

Further pathway enrichment disclosed that calcium signaling pathways and glycosylphosphatidylinositol-anchor biosynthesis were notably affected. Reactome pathway mapping pinpointed 33 altered signaling cascades, prominently featuring TrkA/TrkB, FGFR, and PI3K-AKT networks, all critical for maintaining neuronal excitability and dendritic spine health. These disruptions offer an epigenetic framework for understanding the synaptic deficits observed in stress-related psychiatric disorders.

A network analysis highlighted six hub lncRNAs serving as influential nodes within the stress-responsive transcriptional network. Among these, three—designated ENSG00000225963.8, ENSG00000228412.9, and ENSG00000254211.6—were substantially upregulated under continuous GR activation and displayed enrichment in both PRC2 and histone methylation complexes. These lncRNAs likely represent molecular scaffolds or bookmarks that stably anchor repressive complexes to stress-responsive chromatin regions, thus perpetuating transcriptional silencing beyond immediate hormonal signaling.

This research not only deepens the mechanistic understanding of how glucocorticoid signaling epigenetically silences key neuronal genes but also opens promising translational avenues. The distinct lncRNA signatures identified could serve as biomarkers reflecting an individual’s cumulative stress burden or vulnerability to psychiatric illness. Moreover, targeting the interactions between lncRNAs and PRC2 presents an innovative therapeutic strategy, potentially enabling reactivation of silenced neuroplasticity genes that current antidepressants—focused predominantly on neurotransmitter modulation—fail to address promptly.

Given that the study utilized a controlled in vitro cellular system, researchers emphasize the necessity for cautious extrapolation to human brain physiology. Future efforts must validate these findings in more complex models, including brain organoids derived from patients with depression, and investigate whether circulating lncRNA fragments may serve as accessible proxies for brain stress responses. Functional experiments manipulating candidate lncRNAs will be critical to establish causality in chromatin remodeling and behavioral outcomes.

This transformative work underscores a paradigm shift in psychiatry, encouraging a view of mental health disorders as disturbances not only of neural activity but of cellular memory embedded within the chromatin code. By bridging endocrinology and epigenomics through the novel GR–lncRNA–PRC2 axis, the study exemplifies how integrative, multidisciplinary approaches can unravel the molecular intricacies linking environmental stress to persistent genomic reprogramming.

The robust integrative methodology—combining transcriptomic profiling with chromatin-level RNA immunoprecipitation sequencing—provides a replicable framework for uncovering epigenetic regulators with nearly unprecedented resolution. Beyond enriching basic scientific knowledge, these insights raise hope for innovative biomarker development and rational design of next-generation treatments that enhance stress resilience by modulating genome architecture directly.

Such advances reflect a broader trend in neuroscience, where dissection of noncoding RNA functions is revolutionizing our grasp of gene regulation complexity. The identification of lncRNAs as critical arbiters of stress-induced chromatin remodeling affirms their emerging significance not merely as transcriptional bystanders but as active, functionally indispensable genomic architects with profound implications for brain health.

In sum, the University of Alabama team’s discovery of lncRNA-mediated chromatin silencing triggered by glucocorticoid receptor overexpression stands as a milestone in neuroepigenomics. Beyond establishing a mechanistic link between stress hormone signaling and durable gene repression, this research lays a foundational stone toward precision psychiatry, one that recognizes and exploits the epigenetic alphabet through which stress inscribes its legacy on the brain’s genome.

Subject of Research: Cells

Article Title: Role of lncRNAs in stress-associated gene regulation following chromatin silencing: Mechanistic insights from an in vitro cellular model of glucocorticoid receptor gene overexpression

News Publication Date: 4-Nov-2025

Web References:

https://doi.org/10.61373/gp025h.0107

https://doi.org/10.61373/gp025d.0110

References: The study is published in Genomic Psychiatry, a peer-reviewed journal.

Image Credits: Yogesh Dwivedi

Keywords: long noncoding RNA, lncRNA, glucocorticoid receptor, PRC2, chromatin silencing, epigenetics, stress, neuroepigenomics, transcriptional repression, depression, major depressive disorder, neuronal gene regulation

Tags: chromatin architecture and gene regulationchromatin-bound RNAs and gene silencingglucocorticoid receptor activation and brain functionHPA axis and stress biologyimplications for major depressive disorderlasting effects of stress on neuronal geneslong noncoding RNAs in stress responsemolecular mechanisms of psychiatric disordersrole of PRC2 in gene regulationstress hormones and their impact on gene expressionunderstanding stress biology through RNA interactionsUniversity of Alabama at Birmingham research findings