Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract and are primarily driven by activating mutations in KIT or PDGFRA . A clinically important subset of KIT /PDGFRA wild-type GISTs harbors alterations affecting succinate dehydrogenase subunit genes, which are associated with distinct biology and epigenetic profiles. The introduction of tyrosine kinase inhibitors has transformed their management, yet resistance and recurrence remain major challenges. Increasing evidence indicates that epigenetic processes contribute to tumor initiation, progression, and therapeutic escape. Aberrant promoter methylation has been linked to silencing of tumor suppressor genes, histone modifications reshape transcriptional networks governing proliferation and apoptosis, and chromatin remodeling complexes influence lineage-specific transcription and resistance pathways. Clinical observations further demonstrate that alterations such as SETD2 loss, KDM6A downregulation, or PHH3 overexpression correlate with prognosis, while early-phase trials of histone deacetylase inhibitors illustrate therapeutic feasibility. This review synthesizes current preclinical and clinical evidence on epigenetic regulation in GIST, focusing on DNA methylation, histone modifications, and chromatin remodeling, and explores their translational implications for prognosis and therapy.

Cancer cells reprogram their metabolism not only through genetic mutations but also via reversible epigenetic modifications that alter gene expression without changing the DNA sequence. AMP-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis. It plays a crucial role in cancer by modulating key metabolic pathways, including autophagy, lipid biosynthesis, and glucose utilization. Emerging evidence suggests that AMPK is tightly regulated by epigenetic mechanisms, including DNA methylation, histone remodeling, and non-coding RNAs, which influence AMPK gene expression, activation, and post-translational stability. Non-coding RNAs, including long non-coding RNAs, microRNAs, and circular RNAs, often engage in dynamic feedback loops with AMPK, coupling metabolic stress to transcriptional and epigenetic remodeling. In parallel, DNA methylation and histone modifications influence AMPK signaling indirectly through modulation of upstream regulators and directly via chromatin-associated functions of AMPK. Despite extensive characterization of AMPK function in cancer metabolism, the epigenetic mechanism governing its regulation remain comparatively underexplored. Distinct epigenetic signatures associated with AMPK regulation are being explored as a potential therapeutic target. This review provides a comprehensive overview of epigenetic regulation of AMPK in cancer and highlights its potential in the context of metabolic reprogramming and precision oncology.

Comprehensive mass spectrometry screening-derived atlas of HDAC inhibitors reveals histone-specific acetylation changes.

Aluminum (Al), as a ubiquitous environmental pollutant, has been implicated in the pathogenesis and progression of various neurodegenerative diseases due to its neurotoxic properties. Recent studies indicate that aluminum exposure may induce aberrant epigenetic modifications, thereby disrupting gene expression patterns and cellular functions, ultimately leading to neuronal damage. This review focuses on examining the cross-hierarchical regulatory mechanisms of aluminum exposure on DNA methylation, histone modifications, noncoding RNAs, and RNA modifications. We point out an issue in current research-the isolated analysis of individual epigenetic modifications often neglects their network-based cascade effects. Future investigations should focus on integrating multi-omics approaches with dynamic modeling to elucidate the hierarchical transmission mechanisms underlying epigenetic crosstalk.

Maternal Methionine Nutrition and Its Functions in Epigenetic Regulation of Offspring Development in Animals.

NY-ESO-1 in Triple-Negative Breast Cancer: Systematic Review, Meta-Analysis, and Immunotherapeutic Implications.

Globally, third leading cause of cancer-related deaths is contributed by Hepatocellular carcinoma (HCC). Chronic hepatitis B virus infection is one of the seminal etiological drivers of HCC. Hepatitis B viral DNA integration, host genomic instability, persistent inflammatory responses and the oncogenic activity of the viral oncoprotein Hepatitis B virus X (HBx), contribute to the hepatocarcinogenesis. Emerging evidences indicate that epigenetic dysregulation plays a seminal role in linking viral persistence in the liver tissue to its malignant transformation. In HBV-infected hepatocytes, aberrant DNA methylation, histone modifications, and dysregulated non-coding RNAs reprogram transcriptional networks that activate oncogenic pathways, promote proliferative signaling, and sustain cancer stem cell-like phenotypes driving HCC progression. The epigenetic modifications in the infected, malignant hepatic cells can influence the tumor microenvironment, contributing to the infiltration of exhausted cytotoxic T lymphocytes with elevated PD-1 and Tim-3 expression. Further, the T lymphocytes exhibit reduced proliferative capacity, impaired cytokine secretion, and diminished cytotoxic activity. In the clinical perspective, long-term nucleotide analogue therapy causes viral suppression and attenuation of inflammation, thereby reducing HCC progression by 40-80%. Despite the extensive T-cell exhaustion, HBV-associated HCC (HBV-HCC) is responsive to immune checkpoint blockade, as highlighted in the CheckMate-040 trial. Emerging therapeutic strategies combine anti-viral agents with immune checkpoint inhibitors, epi-drugs and HBsAg-directed TCR-engineered T cells. These clinical approaches aim to simultaneously restore antitumor immune responses as well as neutralize the viral oncogenic drivers, offering promising avenues for improved management of HBV-induced HCC.

Histone H2A deubiquitinase BAP1 is required for human neuronal progenitor cell formation.

Histone modifications of H3K9ac and H4K5ac in a single-cell C4 halophyte in response to light and salt stress

Serotonergic psychedelics as epigenetic modulators: A paradigm shift in Alzheimer's disease therapeutics.

Impact of vitamin D deficiency on defective endometrial decidualization and the repressive role of vitamin D receptor (VDR) in the epigenomic network.

Decidualization is essential for embryo implantation and maintenance of pregnancy, during which quiescent endometrial stromal fibroblasts proliferate and differentiate into decidual stromal cells. Emerging evidence indicates that epigenetic regulators, including histone modifications, play critical roles in uterine receptivity, implantation, and stromal cell decidualization. Our previous study demonstrated that loss of histone deacetylase 3 (HDAC3) impairs endometrial receptivity and decidualization, resulting in female infertility. However, the genome-wide transcriptomic alterations responsible for defective decidualization in loss of HDAC3 remain unclear. In this study, uterine-specific Hdac3 knockout (Pgrcre/+Hdac3f/f; Hdac3d/d) mice exhibited decidual defects following 3 days of artificial decidualization. RNA sequencing analysis of uteri from control and Hdac3d/d mice revealed widespread dysregulation of genes and pathways associated with decidualization. Pathway analysis identified significant alterations in RHOA, AMPK-NOTCH1-HEY1, and oxidative stress-induced senescence signaling, implicating dysregulation of cytoskeletal remodeling, cellular metabolism, and oxidative stress responses in the HDAC3-mediated decidual response. Notably, expression of Limk1, Prkag1, and Cbx2 for key regulators of these pathways was significantly reduced in Hdac3d/d mice compared with controls. These findings demonstrate that HDAC3 is a key regulator of the transcriptional and signaling networks required for successful decidualization. Collectively, our study provides a comprehensive transcriptomic profile of HDAC3-deficient uteri and uncovers key molecular mechanisms underlying impaired decidualization, thereby advancing our understanding of uterine function and pregnancy establishment.

With the advent of spatial multi-omics, mosaic integration of diverse datasets with partially overlapping modalities enables the construction of comprehensive multimodal spatial atlases from heterogeneous sources. Here we present SpaMosaic, a tool that uses contrastive learning and graph neural networks to build a modality-agnostic, batch-corrected latent space for spatial domain identification and missing-modality imputation. We systematically benchmarked SpaMosaic against existing integration methods using simulated data and experimentally acquired datasets spanning RNA and protein abundance, chromatin accessibility and histone modifications from brain, embryo, tonsil and lymph node tissues. SpaMosaic consistently outperformed other methods in identifying coherent spatial domains by reducing noise and mitigating batch effects. We further challenged SpaMosaic with heterogeneous real-world datasets spanning different technologies, developmental stages, resolutions and modality compositions, where it consistently resolved fine anatomical structures and enabled comprehensive mouse embryo atlasing. Beyond integration, SpaMosaic enables accurate imputation of missing modalities. In a mosaic mouse brain dataset, the imputed histone modifications not only recapitulated expected transcriptome-epigenome correlations but also uncovered more region-specific regulatory links compared to the measured chromatin accessibility data, demonstrating the ability to infer relationships across modalities without coprofiling. Computationally, SpaMosaic is highly scalable, capable of integrating over 100 sections and processing a single section with more than 800,000 spots. In summary, SpaMosaic provides a versatile framework for unifying the rapidly accumulating heterogeneous spatial omics data into comprehensive biological atlases.

Prenatal methamphetamine exposure increased addiction vulnerability through neural circuit dysfunction and epigenetic modifications in offspring.

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.

A time-resolved atlas of histone modifications during mitotic entry.

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.

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.

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.