Histone modifications play a fundamental role in epigenetic regulation. Histone methylation mediated by enzymes like absent, small, or homeotic discs 1-like (ASH1L) has emerged as a critical process in normal cellular function and disease, particularly cancer. ASH1L, a member of the Trithorax-group (TrxG) protein family, acts as a histone methyltransferase with the ability to establish H3K36 dimethylation (H3K36me2). In recent years, an increasing number of studies have focused on the dysregulation of ASH1L in various tumors and its potential as a therapeutic target. A detailed literature survey was conducted to compile data from PubMed, SciFinder, and ScienceDirect. After screening, data extraction, and descriptive analysis, a series of related articles was retained. This comprehensive review systematically dissects the molecular mechanisms by which ASH1L modulates oncogenic processes in these cancers, emphasizing its roles in transcriptional activation of driver genes, epigenetic reprogramming, cell cycle progression, and maintenance of cancer stem cell properties. Additionally, we summarize current progress in targeting ASH1L for cancer therapy, highlighting challenges and future directions. ASH1L, as a histone methyltransferase, is associated with the tumor microenvironment, and its anti-tumor targeted therapies require further exploration in the future.

The endocannabinoid system (ECS) is a fundamental regulator of brain and body homeostasis, integrating neural, immune, and stress-related signaling pathways. Dysregulation of ECS components, including cannabinoid receptors (CB1 and CB2), endocannabinoids such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes (FAAH and MAGL), has been increasingly implicated in the pathophysiology of neuropsychiatric disorders, including mood, anxiety, psychotic, stress-related, and eating disorders. Altered endocannabinoid signaling contributes to maladaptive stress responses, emotional dysregulation, and impaired synaptic plasticity, highlighting the role of the ECS as a core integrative mechanism. Therapeutic strategies targeting ECS, particularly through FAAH inhibition and the use of plant-derived cannabinoids, such as cannabidiol (CBD), show promise in restoring endogenous homeostasis while minimizing the adverse cognitive and affective effects associated with direct CB1 activation. ECS function and treatment response are further influenced by genetic polymorphisms in CNR1, CNR2, FAAH, and MGLL, as well as epigenetic mechanisms, including DNA methylation, histone modifications, and microRNA regulation. Despite these advances, clinical translation remains limited by interindividual variability, the complexity of ECS interactions, and the relatively small size of existing clinical studies. Future research integrating longitudinal clinical trials with multi-omics approaches is essential to support the development of evidence-based, personalized interventions. Overall, understanding ECS mechanisms and dysregulation provides a valuable framework for the development of targeted therapies in neuropsychiatric disorders.

Neither rodent models nor in vitro studies of human cells adequately describe the molecular ontogeny of human glial progenitor cells (hGPCs). Here, we use scRNA-seq together with scATAC-Seq and CUT&TAG assessment of chromatin accessibility to track the in vitro genesis and in vivo differentiation of hGPCs from pluripotent stem cells (PSCs). In vitro, the hGPC pool comprises 4 transcriptionally distinct subpopulations, each associated with a distinct pattern of chromatin accessibility and histone modification of stage-dependent genes. After the neonatal transplant of these cells into myelin-deficient shiverer mice (MBPshi/shi), they differentiate further as astrocytes and oligodendrocytes. A combination of gene co-expression, motif enrichment, cell-trajectory, cell-cell interaction, and spatial transcriptomic analyses reveals that the host environment potentiates the context-dependent differentiation of the hGPCs, via their activation of distinct gene regulatory networks. Together, these data describe the process and pathways by which human PSC-derived GPCs are generated in vitro and diversify in vivo to mature as astrocytes and oligodendrocytes.

Histone modifications play critical roles in regulating chromatin dynamics and embryonic development. Among these, histone H4 lysine 20 mono-methylation (H4K20me1) is an essential epigenetic mark associated with gene expression and genome stability. However, the reprogramming and functional roles of H4K20me1 in early embryogenesis remain unclear. Here, we map genome-wide distributions of H4K20me1 in mouse, human, and zebrafish early embryos, revealing a broad distribution pattern along with species-specific features. H4K20me1 is predominantly enriched in gene bodies and undergoes dynamic erasure and reestablishment following fertilization. Functional perturbation of SET8, the only known H4K20me1 methyltransferase, results in developmental arrest, highlighting its necessity for embryogenesis. Mechanistically, H4K20me1 is crucial for zygotic genome activation (ZGA), where it regulates RNA synthesis and transcription, and promotes chromatin accessibility. Our findings provide insights into the dynamic reprogramming and regulatory functions of H4K20me1 in early developmental processes.

Synaptic activity results in long-lasting alterations of neuronal properties, which require gene expression regulation. PYK2 is a calcium-activated non-receptor protein tyrosine kinase highly expressed in hippocampal neurons and involved in synaptic functions. PYK2 also shuttles between the nucleus and the cytoplasm. We show that glutamate stimulation induces PYK2 accumulation in the nucleus of hippocampal neurons in culture through activation of NMDA receptors, L-type voltage-gated Ca2+ channels, and calcineurin. NMDA receptor stimulation also increases nuclear location and interaction with PYK2 of methyl-CpG binding domain protein 2 (MBD2), a modulator of histone modifications and nucleosome remodeling. In PYK2-KO neurons, MBD2 nuclear translocation is diminished, acetylation of histone H4-Lys5 is decreased, and methylation of histone H3-Lys4 is increased. The transcriptome is modified in PYK2-KO hippocampus with a decreased expression of genes coding for excitatory synaptic proteins. In cultured neurons, the absence of PYK2 enhances the glutamate-induced downregulation of synaptic protein transcripts related to epilepsy pathophysiology. In wild-type mice, pilocarpine-induced status epilepticus increases PYK2 and MBD2 nuclear localization in hippocampal neurons, especially in CA3. In PYK2-KO mice, aberrant synaptic sprouting and cell death triggered by status epilepticus are reduced in CA3 compared to wild-type littermates. In PYK2-KO neurons in culture, glutamate-induced cell death is attenuated, and this effect is abolished by re-expression of wild-type PYK2 but not of mutated PYK2 unable to translocate to the nucleus. In summary, our study indicates that regulated PYK2 nuclear translocation in hippocampal neurons may facilitate transcription by removing MBD2 from the active chromatin and may contribute to seizure-induced neurotoxicity.

Certain regulatory DNA regions remain accessible even under conditions of widespread chromatin compaction. These regions are often marked by specific protein factors and histone modifications that help maintain their accessibility. Here, we examine the genomic landscape of acetyl-methyllysine (Kacme), a recently discovered histone post-translational modification. Across multiple systems, Kacme is highly enriched at sites of accessible chromatin, including active promoters, enhancers, silencers, and CTCF-binding sites. We find that Kacme is selectively retained at loci that resist condensation during mitosis, marks XIST and escapee regions on the inactive X chromosome in female cells and demarcates the boundaries of broad heterochromatin domains. Kacme-marked insulator elements block heterochromatin spreading and protect adjacent genes from transcriptional repression, even when H3K27me3 levels are pharmacologically elevated through KDM6A/6B inhibition. Taken together, our findings establish the chromatin features associated with Kacme and support a model in which Kacme helps safeguard chromatin accessibility at loci that resist compaction.

Background: Cognitive and psychiatric disorders are caused by a complex interplay between genetic predisposition, environmental exposures, and dynamic molecular regulation in the brain. Animal models provide a controlled environment for examining these mechanisms, and advances in transcriptome and epigenomic technologies have greatly expanded our knowledge of disease-relevant pathways. Objective: This scoping review systematically maps and synthesizes the epigenetic and transcriptomic findings from the established animal models of four neuropsychiatric conditions-autism spectrum disorder (ASD), schizophrenia, depression, and Rett syndrome-drawing on a PRISMA-ScR-guided literature search. The review characterizes the breadth of evidence, identifies convergent and divergent molecular pathways, and highlights the translational gaps and therapeutic implications. Methods: Research employing chromatin accessibility testing, genome-wide DNA methylation mapping, single-cell and bulk RNA sequencing, histone modification profiling, and multi-omics integration in mouse and other validated animal models was thoroughly reviewed. A quality appraisal of the primary experimental studies (n = 63) was performed using a modified CAMARADES checklist. Results: Beyond generalized cellular stress responses, multi-omics analysis emphasizes the cell-type- and context-dependent nature of epigenetic changes in animal models, including isoform-specific histone modifications and model-dependent binding of HDAC/MeCP2 complexes to genes involved in synaptic plasticity. Single-cell RNA sequencing analyses have uniformly shown transcriptional changes in parvalbumin-positive (PV+) interneurons. Conclusions: The specific convergence of epigenetic disruptions in neural circuits involved in synaptic structure and inhibitory function could play a role in the generation of neuropsychiatric phenotypes in animal models, highlighting the importance of circuit- and cell-type-specific epigenetics while pointing to potential therapeutic avenues.

Establishing a cell type-specific chromatin landscape is crucial for the maintenance of cell identity during embryonic development. However, our knowledge of how this landscape is set during vertebrate embryogenesis has been limited, due to the lack of methods to jointly detect chromatin modifications and gene expression in the same cell. Here we present a multimodal measurement of full-length transcriptome and histone modifications in individual cells during early embryonic development in zebrafish. We show that before the formation of germ layers, the chromatin and transcription states of cells are uncoupled and become progressively connected during gastrulation and somitogenesis. Silencing of developmental genes is achieved by local spreading of repressive chromatin together with cell type-specific demethylation. Combining transcription factor (TF) expression and chromatin states within an interpretable machine learning model, we classify TFs as lineage-specific activators and repressors and identify a subset of TFs that are epigenetically regulated. Altogether, our data resolves the dynamic relationship between chromatin and transcription during early vertebrate development and clarifies how these two layers interact to establish cell identity.

Establishing a cell type-specific chromatin landscape is crucial for the maintenance of cell identity during embryonic development. However, our knowledge of how this landscape is set during vertebrate embryogenesis has been limited, due to the lack of methods to jointly detect chromatin modifications and gene expression in the same cell. Here we present a multimodal measurement of full-length transcriptome and histone modifications in individual cells during early embryonic development in zebrafish. We show that before the formation of germ layers, the chromatin and transcription states of cells are uncoupled and become progressively connected during gastrulation and somitogenesis. Silencing of developmental genes is achieved by local spreading of repressive chromatin together with cell type-specific demethylation. Combining transcription factor (TF) expression and chromatin states within an interpretable machine learning model, we classify TFs as lineage-specific activators and repressors and identify a subset of TFs that are epigenetically regulated. Altogether, our data resolves the dynamic relationship between chromatin and transcription during early vertebrate development and clarifies how these two layers interact to establish cell identity.

Establishing a cell type-specific chromatin landscape is crucial for the maintenance of cell identity during embryonic development. However, our knowledge of how this landscape is set during vertebrate embryogenesis has been limited, due to the lack of methods to jointly detect chromatin modifications and gene expression in the same cell. Here we present a multimodal measurement of full-length transcriptome and histone modifications in individual cells during early embryonic development in zebrafish. We show that before the formation of germ layers, the chromatin and transcription states of cells are uncoupled and become progressively connected during gastrulation and somitogenesis. Silencing of developmental genes is achieved by local spreading of repressive chromatin together with cell type-specific demethylation. Combining transcription factor (TF) expression and chromatin states within an interpretable machine learning model, we classify TFs as lineage-specific activators and repressors and identify a subset of TFs that are epigenetically regulated. Altogether, our data resolves the dynamic relationship between chromatin and transcription during early vertebrate development and clarifies how these two layers interact to establish cell identity.

The Epstein-Barr virus (EBV) is a human gamma-herpesvirus which infects over 90% of the global population and is associated with lymphoid and epithelioid cancers. After infection, EBV enters a latent state in B cells, whereby the viral genome persists as a nuclear episome maintained by expression of a small number of latency-associated viral proteins. The lytic viral proteins, required for DNA replication and virion production, are silenced by cellular epigenetic mechanisms. The immediate-early lytic gene BZLF1 is the most important target for transcriptional repression, as its expression triggers the lytic cascade. To gain insight into the factors restricting BZLF1 expression, we used the PICh method of locus-specific proteomics (proteomics of isolated chromatin segments) to identify proteins which occupy BZLF1 promoter DNA. We identified more than 30 proteins associated with the BZLF1 promoter, including the nucleosome remodeler CHD4 and components of the Polycomb PRC1 complex. We show that CHD4 and PRC1 components are novel repressors of BZLF1 gene expression and that both are required to prevent spontaneous lytic reactivation in Burkitt lymphoma cells. We also reveal a marked, cell-wide loss of the PRC1 histone mark (H2AK119Ub) during the lytic cycle, which is dependent on immediate-early and early lytic gene expression. A proteomic analysis of Burkitt lymphoma cells containing lytic EBV identified upregulation of USP17, a de-ubiquitinase capable of H2AK119Ub removal. Taken together, our study demonstrates the power of proteomic approaches to identify repressors of EBV reactivation and provides new insight into how EBV manipulates epigenetic mechanisms during the lytic cycle.IMPORTANCEFollowing infection, Epstein-Barr virus persists in a latent state where the viral genome resides in the cell nucleus as an episome. Cellular epigenetic proteins occupy the episomes to restrict viral gene expression and prevent lytic reactivation. In this study, we use mass spectrometry to characterize cellular proteins occupying a key viral lytic gene promoter (pBZLF1). We identify the nucleosome remodeler CHD4 and histone modifier complex PRC1 as novel repressors of pBZLF1 and show that both are required to prevent spontaneous EBV lytic reactivation in B cells. We also report that PRC1-mediated histone modification is erased during EBV lytic reactivation from both cellular and viral genomes. The human de-ubiquitinase enzyme USP17 is likely to be responsible for this effect, as upregulation of USP17 is induced by EBV lytic proteins. This study provides new insight into how EBV manipulates epigenetic mechanisms to regulate latency and lytic reactivation and reveals novel potential therapeutic targets.

Although a variety of novel strategies have been used to select antibody-producing cells efficiently either from natural B cell collections or from plasma cell collections postimmunization, the production of monoclonal antibodies against weak antigens with high affinity and special epitopes for diagnostic or therapeutic applications remains fraught with challenges and uncertainty. In this report, we proposed an effective method for generating monoclonal antibodies from rabbits by using histone deacetylase inhibitor (HDACi) to improve antibody gene diversity, particularly the diversity of the complementarity-determining regions (CDRs) which determines the specificity of the antibody. HDACi was encapsulated in nanoliposomes to form an immunomodulator, which was administered to neonatal rabbits during the ontogeny of the immune systems. It was observed that the number of antigen-specific plasma cells in these treated rabbits was increased, and more importantly, the antibody gene diversity, especially the CDRs, was proven to have increased after 3 times of antigen immunization compared with the untreated group, probably due to the promoted efficiency of gene conversion. The results indicated that the histone modification mediated by HDACi treatment has an effect of promoting diversification of the antibody genes in treated animals. The nanoliposomes as a carrier of HDACi helped to increase the utilization rate of the loaded drugs, reduce the total dosage of administrations, and extend the time interval between administrations, making the drug feasible for newborn animals. This new method enables animals to generate antibodies against different epitopes of weakly immunogenic antigens, such as peptide antigens, and makes it possible to select antibodies with better performance for subsequent application in diagnostic reagents.

Abstract Multiple sclerosis (MS) is an immune-mediated, long-term disease of the central nervous system and a leading cause of neurological disability. Despite rapid progress in genome-wide association studies leading to the identification of 233 genetic risk loci for MS susceptibility, the genetic determinants of MS severity remain unclear. To date, only one genome-wide significant locus has been reliably linked to MS severity. Moreover, several observational and Mendelian randomisation (MR) studies have investigated the relationship between environmental and lifestyle factors and MS severity, but the results have been inconsistent. This review summarises the current evidence on both genetic and nongenetic risk factors for MS severity. It also explores potential explanations for the lack of genetic variants associated with MS severity and discusses the methodological challenges that underlie the contradictory findings between observational studies and MR studies. Finally, his review emphasises the biological significance and potential clinical relevance of the recently discovered MS severity locus in the DYSF–ZNF638 region and considers evidence for epigenetic mechanisms, such as DNA methylation, histone modifications, and noncoding RNAs, that may play key roles in modulating disease severity.

Epigenetic modifications play essential roles in regulating gene expression and maintaining cellular identity. Accumulating evidence suggests that chemical agents can contribute to carcinogenesis through epigenetic alterations, such as changes in DNA methylation and histone modifications, even in the absence of direct DNA damage. Here, we have developed a simple, cost-effective, and quantitative reporter assay, termed the epi-TK assay, to evaluate chemically induced epigenetic alterations. The assay is built upon the thymidine kinase (TK) gene mutation assay, a standardized and widely used in vitro genotoxicity assay for chemical safety evaluation. This system is based on an engineered human lymphoblastoid cell line (mTK6), in which the promoter region of the endogenous housekeeping TK gene is site-specifically methylated using epigenome-editing technology, resulting in stable transcriptional repression. Following chemical exposure, epigenetic perturbations at the TK locus are detected by culturing cells under hypoxanthine-aminopterin-thymidine selection and quantifying the frequency of TK revertant colonies, which reflects restoration of TK gene expression. Using the DNA methyltransferase 1 inhibitor GSK3484862 as a model compound, this protocol demonstrates that the epi-TK assay enables sensitive and quantitative detection of epigenetic state transitions. Importantly, this assay allows bi-directional detection of epigenetic changes, including DNA demethylation events and broader alterations in histone modification landscapes. Together, the epi-TK assay provides a practical and quantitative platform for evaluating epigenetic toxicity, with potential applications in chemical safety assessment frameworks. Key features • This protocol describes testing of the epigenetic effects of chemicals using the mTK6 cell line and a modified version of the TK gene-mutation assay. • By employing a DNA-methylated housekeeping TK gene and colony formation as the readout, the assay enables quantitative epigenetic changes without the need for specialized equipment. • The protocol offers a simple, quantitative, and cost-effective platform that is suitable for routine testing and comparative assessment of multiple compounds.

Epigenetic inheritance of repressed chromatin domains plays a central role in the stable silencing of cell type–specific genes and transposons in eukaryotes. Silent chromatin domains are associated with repressive histone modifications, and their propagation requires a read-write mechanism involving recognition of histone modifications by enzymes that also catalyze them. The recycling of parental histones during DNA replication plays a crucial role in maintaining chromatin states by providing the substrate for read-write enzymes. Here we describe recent advances in understanding how the DNA replication machinery and its associated histone chaperones mediate symmetrical parental histone transfer to newly replicated daughter DNA strands and evidence that this process is required for the epigenetic inheritance of silent chromatin domains.

During its lifetime, the plant undergoes transitions between critical developmental stages, such as seed-to-seedling and adult-to-flowering stages. The changes between stages are strictly controlled by genetic and epigenetic factors that act together during the transition. The developmental transition involves repressing active genes in the first stage and activating genes in the next stage. Thus, repression appears to be essential for terminating the previous developmental program, and among the repressors, the VAL genes play a central role. The VALs are B3-domain DNA-binding proteins that regulate LAFL genes during the seed-to-seedling transition, during which VALs downregulate LAFL expression, thereby terminating the embryogenic program in seedlings. Moreover, the VAL also affects the expression of MIR156C, FLC, or FT in the regulation of flowering. These proteins interact with numerous chromatin remodeling factors, such as PRC1, PRC2, and HDAC, which perform distinct histone modifications, ubiquitination, methylation, or deacetylation to negatively regulate the expression of target genes. This review examines the recent advances in studies on the VALs genetic network, which is involved in the developmental transition via diverse epigenetic mechanisms. Moreover, a future perspective on studies of these essential regulators was discussed.

Cardiovascular diseases (CVD) remain one of the leading causes of morbidity and mortality worldwide, with their prevalence continuing to rise due to population aging. Despite compelling evidence supporting the effectiveness of physical exercise in reducing CVD risk, the molecular mechanisms underlying these protective effects remain insufficiently understood. In recent years, an increasing number of studies have highlighted the key role of epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNA expression, in regulating cardiovascular health. Physical activity serves as a potent epigenetic modulator, inducing long-lasting changes in gene expression and activating signaling pathways associated with cardiovascular function. This mini-review presents current data on the impact of physical exercise on long non-coding RNA expression and their role in the pathogenesis and prevention of CVD. Recent studies confirm that epigenetic modifications induced by physical activity hold significant therapeutic potential for the prevention and treatment of CVD.

Long non-coding RNAs (lncRNAs) interact with chromatin and recruit epigenetic complexes to specific genomic loci, yet their relationship with super-enhancers (SEs), key regulatory elements frequently reprogrammed in cancer, remains unexplored. We developed an integrative pipeline that combines RNA-chromatin contact data (RNA-Chrom), histone modification-lncRNA expression correlation profiles (HiMoRNA peaks), and super-enhancer annotations (SEdb 3.0) to map lncRNA-SE regulatory axes. Applying this framework to SNHG1 in HCT116 colorectal cancer cells, we identified 21 SNHG1-reactive super-enhancers (Ψ-SEs) among 184 cancer-specific SEs, at which SNHG1 physical contacts co-occur with SNHG1-correlated histone modifications (HiMoRNA peaks), predominantly H3K4me1 (permutation p = 0.001, fold enrichment = 2.03). Comparison with 4145 lncRNAs demonstrated that epigenetic correlations alone do not distinguish SNHG1; instead, the addition of the contact layer is required to delineate the Ψ-SE set. Differential expression (DESeq2) and co-expression analyses in 471 TCGA-COAD tumor samples identified 12 Ψ-SE target genes (including CDC20, PDP1, and TOP1) consistently upregulated in both HCT116 cells and patient tumors and positively correlated with SNHG1, with the co-expression signal robust to tumor purity correction. The proposed Ψ/Ω classification provides a generalizable framework for prioritizing super-enhancers at which lncRNA-chromatin interactions may shape the local epigenetic environment across cancer types.

Background/Objectives: Physical activity is one of the most powerful lifestyle factors influencing brain health, with growing evidence supporting its role in promoting neuroplasticity, cognitive function, and resilience to age-related neurological decline. Recent studies indicate that these effects are mediated by coordinated molecular responses involving epigenetics, activity-dependent gene expression, metabolic adaptation, and inter-organ communication pathways. This narrative review synthesizes current knowledge from experimental and clinical studies on the neurogenomic and epigenetic mechanisms underlying exercise-induced brain plasticity. Methods: Literature searches were conducted in PubMed, Scopus, Web of Science, and Google Scholar to identify studies examining neurogenomic and epigenetic mechanisms underlying neuroplasticity and cognitive adaptations in response to exercise, with an emphasis on mechanistic and translational evidence. Results: Available evidence, derived predominantly from animal studies and supported by more limited, often indirect human data, indicates that physical activity induces epigenetic modifications, including changes in DNA methylation, histone modifications, and microRNA expression, which contribute to lasting changes in exercise-responsive genes involved in brain plasticity. These adaptations include the upregulation of key neuroplasticity-related mediators that support neurogenesis, synaptic plasticity, angiogenesis, and metabolic adaptation, alongside the downregulation of pathways linked to neuroinflammation, oxidative stress, and apoptotic signalling. Conclusions: Integrating neurogenomics with systems biology approaches offers promising opportunities to better understand how physical activity influences brain plasticity throughout life. These insights may support the development of personalized exercise medicine to improve cognitive health and reduce the risk of neurodegenerative disorders.

Rimonabant (SR141716A), an inverse agonist of the cannabinoid receptor type 1(CB1), once approved for treating obesity and metabolic disorders, was withdrawn shortly after due to psychiatric and psychological adverse events (PPAEs), including depression and suicidality. Although its primary pharmacological mechanism of action is well-characterized, the molecular basis underlying these neuropsychiatric effects remains unclear. Here, we investigated the epigenetic impact of rimonabant exposure, both in vitro and ex vivo, at therapeutically relevant concentrations and doses, with a focus on histone modifications and DNA methylation. In SH-SY5Y human neuroblastoma cells, after 24 and 96h treatment with 0.01 and 1 µM rimonabant significantly increased global histone H3 and H4 acetylation by 2.7- and 1.4-fold, respectively, without altering global DNA methylation levels. The effects on histone acetylation were partially reversed by a CB1 receptor agonist, indicating a role for CB1 in the observed epigenetic modulation. Rimonabant also decreased histone deacetylases (HDAC) activity and reduced the levels of H3K4me3 and H3K27me3, marks that have been previously identified in psychiatric perturbations. Moreover, 4-week oral administration of 3 or 15mg/kg rimonabant to rats produced region- and dose-specific alterations in H3K4me3, H3K27me3, H3K9ac, and 5-methylcytosine levels across the prefrontal cortex, hippocampus, and nucleus accumbens, in line with epigenetic profiles characteristic of depression, anxiety, and schizophrenia. Collectively, these findings demonstrate that rimonabant disrupts key epigenetic regulatory mechanisms in the brain and support the hypothesis that epigenetic dysregulation contributes to its psychiatric liabilities. This work strengthens the value of incorporating epigenetic endpoints into neuropharmacological safety assessments.