Search Results (1,967)

The hypothalamic–pituitary–adrenal (HPA) axis coordinates metabolic, immune, and behavioral responses to a changing environment. Its molecular effectors are the nuclear receptors for glucocorticoids and mineralocorticoids (the GRs/MRs), encoded by nr3c1/nr3c2. The MR serves as the high-affinity sensor of basal hormone concentrations, whereas the GR amplifies the stress response and mediates negative feedback. Despite their shared domain architecture, the receptors have diverged functionally: isoform composition, post-translational modifications, and the complement of co-regulators together determine which genes are activated or repressed in a given tissue at a given time. The regulation of the HPA axis activity is a major determinant of embryonic development. Pregnancy adds a placental control layer that meters maternal signals: 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) in the syncytiotrophoblast inactivates cortisol, whereas 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) can regenerate it, and systemic buffering by transcortin (cortisol-binding globulin, CBG) limits the free hormone fraction. Under stress, inflammation, or hypoxia, this barrier weakens, exposing the fetus to stronger glucocorticoid pulses during windows of heightened vulnerability for brain and immune development. Such overexposure not only reshapes ongoing transcription but is also epigenetically inscribed: the methylation of alternative nr3c1 promoters, the remodeling of histones, and the shifts in ncRNA profiles recalibrate the axis sensitivity for the long term. At the phenotypic level, this manifests as variability in stress reactivity, cognitive and affective trajectories, and an immune and metabolic risk across later ontogeny. In this review, we integrate evidence on the structure and functions of the GR, the mechanisms of its post-translational and epigenetic regulation, and the role of the placenta, to provide a coherent framework for understanding the multifaceted consequences of prenatal stress and to identify potential targets for early prevention. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, driven by aggressive tumor biology, extensive intratumoral heterogeneity, and profound resistance to standard therapies. While recurrent genetic alterations such as KRAS mutations are central to PDAC initiation, growing evidence demonstrates that epigenetic dysregulation is a critical determinant of disease progression, cellular plasticity, immune evasion, and therapeutic failure. Epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA regulation, shape transcriptional programs without altering the underlying DNA sequence, rendering them dynamic and potentially reversible therapeutic targets. This review provides a comprehensive overview of key epigenetic proteins implicated in PDAC, encompassing writers, readers, and erasers of chromatin marks. Aberrant activity of histone methyltransferases and acetyltransferases, bromodomain-containing proteins, histone deacetylases, and demethylases orchestrates transcriptional reprogramming that promotes epithelial–mesenchymal transition, stem-like phenotypes, metabolic adaptation, and resistance to chemotherapy and radiotherapy. In parallel, epigenetic alterations within the tumor microenvironment contribute to stromal activation and immune suppression, further limiting therapeutic efficacy. We summarize recent advances in pharmacological targeting of epigenetic regulators and discuss the rationale for combination strategies integrating epigenetic inhibitors with cytotoxic agents, targeted therapies, and immunotherapies. Emphasis is placed on emerging experimental platforms—including patient-derived organoids, co-culture systems, and in vivo models—combined with multi-omic profiling and computational approaches to identify biomarkers of response and optimize therapeutic design. Collectively, this review highlights epigenetic regulation as a central and actionable vulnerability in PDAC and outlines future directions toward biomarker-guided, personalized epigenetic therapies aimed at overcoming resistance and improving clinical outcomes. Full article

SIRT7is an NAD⁺-dependent deacetylase predominantly localized in the nucleolus, where it plays important roles in chromatin regulation, transcriptional control, and cellular stress response. Accumulating evidence has revealed that SIRT7 participates in multiple molecular processes, including ribosomal RNA transcription, histone modification, DNA damage repair, metabolic regulation, and inflammatory signaling pathways. Through these mechanisms, SIRT7 contributes to the pathogenesis of various human diseases, particularly cancer and metabolic disorders. In recent years, emerging studies have begun to uncover the roles of SIRT7 in the central nervous system (CNS). Although research in this area remains limited, available evidence suggests that SIRT7 may be involved in neuronal homeostasis, glial function, neuroinflammation, and responses to brain injury. Furthermore, dysregulation of SIRT7 has been implicated in CNS-related pathologies. In this review, we summarize the understanding of SIRT7 molecular mechanisms and its implications in human disease, with special emphasis on its emerging roles in the CNS. We also address unresolved questions and propose future research directions to facilitate a deeper understanding of SIRT7 in neurological physiology and pathology. Full article

The acceleration of climate change poses a growing threat to human health, particularly by exacerbating non-communicable diseases (NCDs) such as cardiovascular and respiratory conditions. Rising global temperatures amplify air pollution and environmental toxins, disproportionately affecting vulnerable populations. This narrative review explores the complex pathways linking climate-related environmental stressors to adverse health outcomes, focusing on the intermediary roles of epigenetic modifications and alterations in the microbiota. Epigenetic processes, including DNA methylation and histone modifications, may mediate how environmental exposures influence gene expression and disease susceptibility. Concurrently, changes in microbiota composition induced by pollutants and temperature fluctuations can promote inflammatory responses and immune dysfunction. Elucidating these molecular mechanisms is essential for developing targeted interventions and adaptive strategies to mitigate the health impacts of climate change. This review underscores the importance of identifying epigenetic and microbiota-based biomarkers for early risk stratification and for informing public health prevention and adaptation policies. A transdisciplinary approach, grounded in the One Health framework, is critical to addressing the growing burden of climate-sensitive diseases and reducing health inequalities. Full article

Background/Objectives: The primary mechanisms driving UV-induced carcinogenesis include DNA damage leading to mutations, and reactive oxygen species (ROS) formation that can cause inflammation, immunosuppression, alteration of the structure of proteins, including transcription factors, and carcinogenesis through epigenetic modifications. Curcumin has the potential to inhibit DNA-methyltransferases (DNMTs) and histone deacetylases (HDACs), but this has not been examined yet at the gene-expression level. In this article, we aimed to explore the potential protective effect of curcumin against UV radiation-induced DNMT1, DNMT3A, DNMT3B, HDAC5, and HDAC6 expression in immortalized keratinocytes (HaCaT), hepatocellular carcinoma (HepG2), and lung adenocarcinoma (A549) cells. Methods: Cells were exposed to UV-B radiation for different periods and treated with curcumin at different concentrations to evaluate dose-related trends in DNMT and HDAC gene expression compared with untreated UV-exposed cells. Results: UV exposure increased the DNMT and HDAC gene expression levels in the examined cells dose-dependently. Curcumin exposure resulted in decreased mRNA expression levels of DNMT and HDAC gene expression. In our experimental setup curcumin modulated the transcription of DNMT and HDAC genes in A549 and HaCaT cells in a dose-dependent manner. In HepG2 cells, UV-B induced a less pronounced, but still significant, increase in the examined gene expression levels. This effect was also dose-dependently decreased by curcumin, although less markedly. Conclusions: Future studies are warranted to examine if curcumin combined with other chemopreventive agents through the HDAC and DNMT inhibitory activity at the gene expression level can exert a synergistic effect and may potentially supplement cancer therapeutic strategies. Full article

The loss of estrogen following menopause is associated with a marked increase in cardiometabolic risk, accompanied by adverse changes in lipid metabolism, insulin sensitivity, vascular function, and systemic inflammatory tone. Emerging evidence suggests that estrogen signaling interacts with chromatin regulatory mechanisms, including DNA methylation, histone modifications, and chromatin remodeling, across multiple metabolic tissues. In this review, we examine current evidence linking estrogen receptor signaling to epigenetic modulation in cardiovascular, hepatic, adipose, vascular, and immune systems. We propose that epigenetic remodeling represents a plausible and testable mechanistic framework connecting estrogen depletion to cardiometabolic disease progression, while acknowledging that much of the mechanistic evidence derives from preclinical and in vitro systems and that direct longitudinal validation in human cardiovascular tissues remains limited. We further explore how this framework may contribute to understanding the “estrogen paradox” and the heterogeneous outcomes of hormone replacement therapy (HRT), particularly within the context of the timing hypothesis. Finally, we evaluate pharmacologic and lifestyle interventions, including structured exercise, dietary modulation, and cardiometabolic therapeutics, through the lens of potential epigenetic influence. Clarifying tissue-specific and immune-integrated chromatin responses to estrogen loss will be essential for advancing precision strategies aimed at improving cardiometabolic health in postmenopausal women. Full article

Enhancer of Zeste Homolog 2 (EZH2), the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), mediates histone H3 lysine 27 trimethylation (H3K27me3), an epigenetic modification associated with transcriptional repression. EZH2 inhibitors (EZH2is) gained attention after the first-in-class drug Tazemetostat received FDA approval for treating epithelioid sarcoma. Preclinical studies suggest that EZH2is could be effective against melanoma, but their general inability to cross the blood–brain barrier (BBB), among others, limits the treatment of secondary brain metastases. Based on these limitations, we designed SG-8, a novel compound derived from TDI-6118 (a known brain-penetrant EZH2i). In silico docking predicted that SG-8 may exhibit high affinity for EZH2 as well as for another PRC2 subunit, Embryonic Ectoderm Development (EED). In addition, in vitro PAMPA assays suggested passive BBB permeability of SG-8. In cell-based assays, SG-8 and the structurally related EZH2i PF-06726304 displayed lower cytotoxicity than Tazemetostat in both primary (A375) and metastatic (Colo-679) human melanoma cells. Western blot analysis showed that SG-8 and PF-06726304 markedly reduced EED protein levels and, to a lesser extent, EZH2 levels, without affecting total H3K27me3, consistent with preserved canonical PRC2 activity. Instead, treatment with both compounds—most prominently SG-8—was associated with reduced phosphorylation levels of EZH2 (Ser21) and its upstream regulator Akt (Ser473), suggesting that modulation of the Akt–EZH2 signaling axis may at least partially contribute to their anti-melanoma activity. Full article

Oral squamous cell carcinoma (OSCC) represents a major global health burden and remains one of the most prevalent and aggressive malignancies of the head and neck region. Despite significant advances in surgical techniques, chemotherapy, and radiotherapy, patient outcomes have improved only modestly over recent decades. The high recurrence rate, metastatic potential, and resistance to therapy underscore the complexity of OSCC biology and the limitations of conventional treatment approaches. In recent years, the concept of cancer stem cells (CSCs) has reshaped the understanding of tumor initiation, progression, and therapeutic failure in OSCC. These cells, characterized by self-renewal capacity and phenotypic plasticity, are believed to sustain tumor growth, drive recurrence, and mediate resistance to therapy. Parallel to this, insights into epigenetic regulation, including DNA methylation, histone modifications, and non-coding RNAs, have revealed new layers of molecular heterogeneity and adaptability in oral carcinogenesis. The integration of CSC biology with epigenetic modulation offers a promising foundation for the development of targeted and personalized therapeutic strategies. Novel approaches aim to eradicate CSCs, induce their differentiation, or reprogram their malignant phenotype through the use of epigenetic inhibitors and molecular modulators. This review summarizes current knowledge on the molecular and cellular mechanisms driving OSCC pathogenesis, highlights the emerging role of CSCs and epigenetic regulators, and discusses the challenges and perspectives of translating these findings into effective clinical therapies. Full article

H3K4me3, a well-established histone modification associated with active promoters, plays a critical role in orchestrating gene expression programs that govern mammary gland development and lactation. In this study, we present the first comprehensive epigenomic profiling of H3K4me3 modifications during mammary gland development in Yili horses using Cleavage Under Targets and Tagmentation (CUT&Tag) and RNA sequencing. Mammary gland tissues were collected from two developmental stages—early lactation and peak lactation. A total of 393 differentially expressed genes (DEGs) were identified between two groups, among which 72 DEGs (54 upregulated H3K4me3 targets and 18 downregulated targets) were directly regulated by H3K4me3. KEGG enrichment analyses revealed that these DEGs were involved in ECM–receptor interaction, focal adhesion, the PI3K-Akt signaling pathway, and the calcium signaling pathway. In these pathways, five genes were identified as potential regulators of mammary gland development. Among these, PTGES, COL1A1, PDGFRB, and RYR1 exhibited consistent upregulation at both the transcriptomic and chromatin levels, whereas PRKAG3 showed significant downregulation. These findings offer novel insights into the epigenetic regulation of lactation in horses and lay a theoretical foundation for improving milk production traits through targeted molecular breeding strategies. Full article

Early-life respiratory viral infections represent a major global health burden and are key determinants of long-term susceptibility to chronic respiratory diseases. In neonates the immaturity of the immune system contributes to the high incidence and severity of these infections. Because humans are born with a mainly naive adaptive immune system, the host protection in early life greatly relies on the innate immune cells. Interestingly, innate immune cells have been recently shown to develop traits of immune memory. Both adaptive and innate immune memory formation are, among others, mediated by epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNAs. This review comprehensively analyzes evidence of the changes in epigenetic modifications before and after respiratory infection in childhood. Understanding how epigenetic programming modulates immune cells in early life may open new avenues for preventive interventions to respiratory viral infection, enhancing antiviral defense in infancy and reducing the long-term consequences of respiratory infections. Full article

Phosphorylation has long been regarded as the principal mechanism governing oncogenic signal transduction. However, it does not fully account for the diversity, persistence, and context dependence of cancer signaling outputs. Protein methylation, historically studied in the context of histone regulation, is now recognized as a widespread modification of non-histone signaling proteins, including transcription factors, DNA damage response mediators, and scaffold components. In this Review, we propose that protein methylation functions as a regulatory logic layer that shapes how oncogenic signals are amplified, stabilized, and interpreted. Rather than serving as a primary trigger of pathway activation, methylation modulates signaling behavior across four interconnected dimensions: activation threshold and signal gain, temporal persistence, network topology and complex assembly, and spatial routing. We examine major signaling axes in which methylation refines genome integrity networks, proliferative pathways, inflammatory circuits, and lineage-specific transcriptional programs. We further discuss the interdependency between methylation and phosphorylation, highlighting sequential, competitive, and feedback-mediated interactions that expand combinatorial signaling states. Finally, we explore how methylation-mediated regulatory logic contributes to signaling plasticity and adaptive resistance under therapeutic pressure, and we outline key measurement and translational challenges. Framing protein methylation within a regulatory logic paradigm provides a structured approach for integrating this modification into contemporary models of oncogenic signaling and therapeutic intervention. Full article

Eukaryotic DNA is wrapped around octamers of four core histones, forming nucleosomes. Histone post-translational modifications (PTMs) influence chromatin structure and the recruitment of regulatory factors, thereby affecting gene expression and DNA repair, including the response to DNA double-strand breaks (DSBs). Here, we describe a robust chromatin immunoprecipitation protocol combined with micrococcal nuclease digestion and DNA sequencing (MNase-ChIP-seq) to map histone modifications and their genome-wide distribution after the induction of a single DSB by the HO endonuclease in Saccharomyces cerevisiae. We validate the method by detecting changes in histone H3 methylation following HO transcriptional activation and DSB induction. This protocol enables reliable analysis of histone PTMs across mutant strains or stress conditions, supporting studies of chromatin dynamics in yeast. Full article

Background/Objectives: Fire is a dominant ecological force in Mediterranean ecosystems, shaping the adaptive traits of forest species such as Pinus brutia. Prescribed burning (also called controlled burning) is the intentional, carefully planned use of fire under specific environmental conditions to manage vegetation and reduce wildfire risk. While morphological and physiological fire adaptations are well-documented, emerging evidence highlights the role of epigenetic mechanisms—such as DNA methylation and histone modifications—in mediating stress responses. Methods: This study investigates genome-wide epigenetic changes in P. brutia following a prescribed burning experiment on Chios Island, Greece. Using methylation-sensitive amplified polymorphism (MSAP) analysis, we compared temporal shifts on epigenetic profiles before and after fire exposure extracting DNA from the same trees. Results: A significant increase in polymorphic epiloci, epigenetic diversity indices, and private epigenetic bands after prescribed burning was revealed, suggesting a stress-induced reprogramming of the epigenome. Concurrent measurements of midday needle water potential indicated an exploratory association between water stress and epigenetic shifts. Furthermore, Fireline Intensity (FI) correlated with epigenetic diversity index signaling an immediate response of the tree. Conclusions: These findings support the hypothesis that fire stress induces epigenetic responses in P. brutia, potentially enhancing resilience to future environmental challenges. Further research is required to address the level of heritability of these epigenetic changes in next generation and connect these indexes with adaptation and sustainability of forest ecosystems. Full article

Colorectal cancer (CRC) is a significant cause of cancer mortality in the world, and its etiology is complicated by genetic and epigenetic changes. As one of the most important tumor progression regulators, Zinc Finger E-box Binding Homeobox 1 (ZEB1) is a transcription factor that has a key role in epithelial–mesenchymal transition (EMT), which is essential in the metastasis, drug resistance, and plasticity of cancer cells in CRC. ZEB1 silences the expression of epithelial markers, including E-cadherin, and it induces the development of mesenchymal properties, such as invasion and metastasis, i.e., tumor aggressiveness. ZEB1 drives epigenetic reprogramming in CRC by coordinating histone deacetylation, histone methylation, and DNA methylation of epithelial tumor suppressor gene promoters and by engaging in reciprocal regulatory interactions with non-coding RNAs, including the miR-200 family. Furthermore, multiple oncogenic signaling cascades, including Wnt/β-catenin, TGF-β, NF-κB, MEK-ERK, JAK/STAT3, and HIF-1α, converge on ZEB1 to amplify its transcriptional and epigenetic activity, positioning ZEB1 as a nodal integrator of extracellular cues and epigenetic reprogramming in CRC metastasis. This review integrates three interconnected regulatory layers, i.e., (1) ZEB1’s direct epigenetic control of target gene expression via histone modification and DNA methylation, (2) post-transcriptional regulation of ZEB1 itself by ncRNAs (miRNAs, circRNAs, and lncRNAs) that create feedback circuits modulating layer 1, and (3) upstream modulation of ZEB1 transcriptional activity by oncogenic signaling pathways (Wnt/β-catenin, TGF-β, NF-κB, MEK-ERK, JAK/STAT3, and HIF-1α) to provide a comprehensive picture of ZEB1 in CRC metastasis and its therapeutic implications. Full article

The important economic traits of ruminants result from interactions between genetic background and environmental factors, but key traits such as reproductive performance, feed efficiency, disease resistance, and livestock product quality are often not fully explained by DNA sequence variations alone. Increasing evidence suggests that epigenetic regulation serves as a crucial molecular bridge connecting environmental stimuli with changes in gene expression, allowing organisms to exhibit stable and plastic phenotypic differences without altering the DNA sequence. This review provides a structured synthesis of recent research in the field of epigenetics in ruminants, elucidating how multiple layers of epigenetic mechanisms, including DNA methylation, histone modifications, non-coding RNAs, and higher-order chromatin structures, coordinate to regulate growth, development, reproductive performance, metabolic and immune homeostasis, and livestock product traits across different tissues and developmental stages. These epigenetic marks not only demonstrate high responsiveness to nutrition, management, and environmental stressors, but can exhibit context-dependent stability within the same tissue and physiological stage when environmental conditions are comparable, thereby contributing to the regulation of phenotypic plasticity and offering potential value as predictive biomarkers. Furthermore, epigenetic information can supplement our understanding of phenotypic variation in ways that traditional genomic selection methods are unable to capture, offering new data dimensions for the prediction and improvement of low heritability, environmentally sensitive traits. Overall, integrating epigenetic information with genomic selection strategies may improve the accuracy of ruminant trait prediction and enhance environmental adaptability. This integration also offers a conceptual basis and technical pathway for developing more precise and sustainable breeding systems. Full article