Yogesh Dwivedi

Epigenetic and epitranscriptomic mechanisms work together to control gene expression, which is essential for brain development, synaptic plasticity, and the risk of neuropsychiatric disorders. Traditional epigenetic processes, such as DNA methylation and histone modifications, alter chromatin structure to regulate gene accessibility. On the other hand, epitranscriptomic marks such as N6-methyladenosine (m6A) affect RNA metabolism after transcription. Studies in both neural and non-neural systems show that these layers of regulation interact in both directions and together shape gene expression. This review looks at how m6A-modified non-coding RNAs, including chromosome-associated regulatory RNAs (carRNAs), enhancer RNAs (eRNAs), microRNAs, and circular RNAs, work with chromatin to influence genome function, including chromatin accessibility, histone modifications, and the overall structure of the genome. It also covers recent discoveries about how eRNAs form R-loops, how m6A affects RNA stability, and how these processes are involved in neuronal signaling and plasticity. Many of these findings come from studies outside the nervous system and need more research in neuropsychiatric disease models. By bringing together established knowledge and new ideas, this review suggests that the interaction between epigenetic and epitranscriptomic mechanisms is a key factor in determining risk and resilience for neuropsychiatric disorders, and offers new directions for future research and therapy development.

Activity-dependent gene regulation is fundamental to synaptic plasticity, and its disruption is increasingly recognized as a feature of major depressive disorder (MDD). Environmentally driven changes in gene expression can alter neural plasticity in corticolimbic brain regions, yet the post-transcriptional mechanisms linking environmental stress to maladaptive neuronal function remain incompletely understood. RNA epitranscriptomic regulation has recently emerged as an important layer of gene control, with N6-methyladenosine (m6A) representing the most abundant and dynamically reversible internal modification of mammalian mRNA. Widely present in the adult brain, m6A regulates RNA splicing, export, stability, localization, and translation, thereby shaping transcript fate and protein output. Although m6A RNA methylation has been studied extensively in other biological contexts, its contribution to MDD pathophysiology is only beginning to be defined. Current human evidence is primarily correlative, derived largely from bulk-tissue postmortem datasets, and should be considered hypothesis-generating until replicated in independent cohorts and validated with cell-type-resolved and mechanistic approaches. Emerging clinical and preclinical studies suggest that dysregulated m6A signaling may influence neurodevelopmental, neurocognitive, and stress-responsive pathways relevant to depression. By integrating environmental signals with transcriptomic regulation, m6A modification may represent a plausible epitranscriptomic mechanism governing synaptic plasticity in the depressed brain. In this review, we summarize the dynamic regulation of m6A RNA methylation in the brain, discuss its neurobiological functions, and critically evaluate its potential role in stress-related pathology and MDD.

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.

Aim: Major depressive disorder (MDD) is a leading cause of disability and carries a high risk of suicide. MicroRNAs (miRNAs) are epigenetic regulators implicated in MDD and can be regulated by DNA methylation, potentially reshaping downstream gene networks. We investigated methylation‐linked miRNA dysregulation and explored whether these changes are specifically associated with suicide among MDD patients. Methods: Genome‐wide DNA methylation profiling of the dorsolateral prefrontal cortex from 15 MDD patients who died by suicide (MDD+S), 17 MDD patients who died from causes other than suicide (MDD−S), and 16 controls (C) using the Illumina 850K MethylationEPIC array was integrated with small RNA sequencing‐based miRNA quantification to identify miRNA‐associated differentially methylated probes (DMPs), link methylation to miRNA expression, and infer downstream targets and pathways. Results: Differential methylation analysis ( P ≤ 0.05) revealed 139 miRNA‐linked DMPs in C vs. MDD+/−S, 135 in C vs. MDD−S, 179 in C vs. MDD+S, and the highest in MDD+S vs. MDD−S (235). CpG‐miRNA pairing (within 1500kb promoter) followed by Spearman correlation identified inverse associations between CpG β values and miRNA expression, with the most consistent signals in suicide‐status‐stratified subsets, including cg06341821‐hsa‐miR‐574‐3p and cg25451306‐hsa‐miR‐2110 in MDD+S‐related contrasts, and cg06179179‐hsa‐miR‐595 in MDD−S‐related contrasts. High‐confidence target prediction and ClueGO enrichment indicated distinct biology: miR‐595 target genes in MDD−S were enriched for interferon/innate immune signaling, whereas miR‐2110 target genes in MDD+S were enriched for ligand‐gated ion channel activity and synaptic/receptor signaling. Conclusion: This integrated approach identifies methylation‐regulated miRNA pathways that may play key roles in the molecular pathogenesis of MDD and suicide.

Chromatin conformational changes are key to gene regulation in the brain and have recently been shown to be regulated by super-enhancer RNAs (seRNAs). We examine the role of seRNAs in major depressive disorder (MDD) by profiling the prefrontal cortex from 25 MDD subjects and 25 matched non-psychiatric controls. Our analysis reveals 175 differentially expressed seRNAs, of which 140 are upregulated and 35 are downregulated. Our proximity mapping (±50 kb) links 94 seRNAs to nearby protein-coding genes, while long-range analysis (±500 kb) uncovered 584 seRNA-mRNA interaction pairs, most within 400 kb of genomic range. These interactions formed cis-regulatory hubs and hotspots, with notable pairs involving CEBPA, NR3C1, and DUSP1. Additionally, several genes are found to be co-regulated by distinct seRNAs. Spatial mapping confirms that many altered seRNAs are located near super-enhancer regions. Our results for the first time highlight seRNAs as key modulators of proximal and distal gene networks in MDD, offering novel insights and therapeutic avenues.

Major depressive disorder (MDD) affects more than 280 million people worldwide and is one of the leading contributors to disability, premature mortality, and overall disease burden. Nearly 60% of individuals who die by suicide have an MDD diagnosis, underscoring its profound impact on both individuals and society. MDD arises from a complex interplay of genetic vulnerability, life experiences, and molecular alterations. Among these, epigenetic mechanisms have received particular attention because they help explain how environmental stress—especially chronic stress—can produce enduring biological changes. MicroRNAs (miRNAs) represent a key class of epigenetic regulators. These small, noncoding RNAs influence the efficiency with which target genes are translated into protein, thereby exerting potent post-transcriptional control over gene expression. Approximately 70% of known miRNAs are expressed in the brain, where they shape neuronal development, synaptic plasticity, and stress responsivity. Dysregulation of miRNA expression can disrupt coordinated gene networks and has been repeatedly associated with impairments in neurogenesis, neurotransmission, neuroinflammation, and endocrine signaling—processes central to the pathophysiology of MDD and other stress-related psychiatric conditions. Within this broader landscape, miR-425 has emerged as a particularly relevant epigenetic regulator across several brain disorders. Alterations in miR-425 expression have been reported in individuals with stress-related conditions and in animal models of chronic stress exposure. Emerging evidence suggests that miR-425 modulates several mood-relevant pathways, including regulation of the hypothalamic–pituitary–adrenal (HPA) axis, neuronal cell death, inflammatory signaling, and antidepressant treatment response as well as key signaling networks such as MAPK and Wnt. Given its regulatory role and disease-associated expression changes, miR-425 has gained significant interest as both a biomarker and a potential therapeutic target. In this review, we examine its biogenesis, molecular targets, and translational importance, positioning miR-425 as a promising candidate for psychiatric intervention strategies. A substantial knowledge gap remains and needs further study. For example, the functions of miR-425 within specific cell types and neural circuits are less defined, and most available evidence derives from rodent studies. Also, the support for miR-425 as a biomarker needs large, standardized, multisite, longitudinal studies integrating neuroimaging, proteomics, and detailed clinical phenotyping. In addition, we are only beginning to understand how pharmacologic and lifestyle interventions influence miR-425 expression. Finally, key downstream targets of miR-425 and safe, cell–type–specific delivery approaches for miR-425–based therapeutics remain underdeveloped. Collectively, these gaps underscore the need for rigorous, multimodal, translational research to determine the potential of miR-425 as both a biomarker and a target for novel treatments.

Global suicide remains a major public health concern, with the World Health Organisation reporting 727,000 suicide deaths in 2021, the third leading cause of death among individuals aged 15–29 (WHO...