Search Results (1,957)

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

Staphylococcus aureus (S. aureus) is the most prevalent pathogen associated with subclinical mastitis, which significantly impacts dairy farming worldwide. Fluctuations in reproductive hormones, such as bovine prolactin (bPRL) and 17β-estradiol (E2), are known to compromise the innate immune response (IIR) of the mammary gland (MG). In this study, we evaluated the effects of bPRL and E2 on the effector response of primary bovine macrophages, isolated from lactating Holstein cows, challenged with S. aureus. We demonstrated that physiological concentrations of bPRL (5 ng/mL) and E2 (50 pg/mL) induced differential changes in the expression of pro-inflammatory (TNF-α, IL-6, and IL-1β) and anti-inflammatory (IL-10) cytokines, chemokines (IL-8), antimicrobial peptides (BNBD10 and S100A7), and miRNAs (miR-451, miR-155, miR-7863, miR-146a, miR-21a, Let-7a-5p, miR-30b, and miR-23a) in S. aureus-challenged macrophages. Moreover, these hormones promoted global histone H3 acetylation and the epigenetic H3K9ac mark without affecting H3K9me2 levels. Hormonal treatment also modulated histone deacetylase (HDAC) activity. Furthermore, hormonal treatment altered macrophage chemotaxis and phagocytosis. In conclusion, bPRL and E2 modulate the effector functions of bovine macrophages during S. aureus infection. This process could be associated with the regulation of histone H3 modifications, such as H3K9ac, in IIR-related genes. Full article

Cell division is a highly regulated process that actively involves dynamic changes to the genetic material within the nucleus. DNA is faithfully replicated in the S-Phase of the cell cycle, being converted from loose, relaxed chromatin into tight, condensed chromosomes to be segregated in mitosis. In addition to scaffolding proteins that shape these mitotic chromosomes, post-translational modifications of histones within nucleosomes modulate chromosome dynamics throughout the cell cycle. In this review, we use a comparative approach to highlight some of the major epigenetic marks affected by the cell cycle during embryogenesis of Caenorhabditis elegans: H4K20me1, H3S10ph, H4S1ph, H2AS1ph, and H3T118ph. These five histone post-translational modifications will be specifically highlighted in the context of the mitotic cell cycle, as they are well documented in the C. elegans literature. Full article

Background/Objectives Sports-related musculoskeletal injuries remain a major challenge in physically active populations, with substantial interindividual variability in susceptibility and recovery that cannot be fully explained by biomechanics or genetics alone. Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs, provide a dynamic interface through which mechanical loading, inflammation, and metabolic signals regulate gene expression during tissue adaptation and repair. This narrative review synthesizes current evidence on “epigenetically active” dietary supplements and their potential relevance to sports injuries, focusing on methyl donors, polyphenols, omega-3 fatty acids, vitamin D, and redox-active nutrients. Methods Targeted searches of PubMed, Scopus, and Web of Science (2000–2026) were performed using epigenetics-, injury-, exercise-, and supplementation-related terms, prioritizing mechanistic and translational evidence. Results Available data indicate that these compounds can influence molecular mechanisms implicated in musculoskeletal recovery. However, human evidence is largely derived from peripheral tissues and indirect molecular markers, with limited clear linkage to clinically significant injury outcomes such as injury incidence, severity, or return-to-play timelines. Accordingly, these nutrients are best viewed as modulators of recovery-related biology rather than as direct therapeutic agents. Conclusions This review highlights a notable translational gap between mechanistic plausibility and clinical evidence and discusses practical implications for sports nutrition from a personalized perspective. Future research priorities include tissue-relevant epigenetic assessments, integration of multi-omics approaches, and longitudinal trials incorporating injury endpoints. Nutritional epigenomics, therefore, represents a promising avenue to support musculoskeletal health while underscoring the need for rigorous clinical validation. Full article

Metabolic reprogramming and epigenetic remodeling are critical features of tumorigenesis. The process of metabolic reprogramming causes metabolites like Succinyl-CoA to accumulate. Succinylation, which depends on succinyl-CoA as the direct donor group, plays a crucial role in regulating cancer metabolism. This involves the transfer of the succinyl group to the lysine residues of substrate proteins resulting in the alteration of the conformation and function of the proteins, modulating several signaling pathways, many of them involved in metabolism. There is growing evidence that succinylation can alter the activity and stability of metabolic enzymes and reshape metabolic networks. Furthermore, it precisely regulates gene expression through the epigenetic modification mechanisms of the histones and non-histone proteins. Lysine succinylation is thus a crucial hub linking tumor metabolic reprogramming and epigenetic remodeling. This review systematically summarizes the dynamic regulatory mechanisms of lysine succinylation and its critical roles in tumor metabolic reprogramming and epigenetic regulation. In the end, we discuss the crosstalk between succinylation and other post-translational modifications (PTMs) as well as recent advances in cancer therapies targeting succinylation. Full article

Human preimplantation embryo arrest (PREMBA) represents a significant clinical hurdle in assisted reproductive technology (ART), in which approximately 10% of in vitro fertilized (IVF) embryos arrest at the cleavage stages. Whole-exome sequencing (WES) studies have discovered numerous genetic mutations associated with preimplantation embryo arrest. These mutations often disrupt critical biological milestones such as maternal mRNA clearance (BTG4, ZFP36L2, ZAR1), subcortical maternal complex (TLE6, PADI6, OOEP, NLRP2, NLRP5, NLRP7, KHDC3L), DNA double-strand break formation and homologous recombination (REC114, TOP6BL, MEI1, MEI4, TRIP13), spindle assembly (TUBB8 and TUBA4A) and cell cycle and checkpoints (FBXO43, MOS, CHEK1, TRIP13, CDC20), as well as nuclear transport and translational regulation (KPNA7, DDOST). However, the cause of most clinical cases remains genetically unexplained. Studies investigating these unexplained arrests have uncovered widespread multi-omics abnormalities, including transcriptional arrest, DNA hypermethylation, higher chromatin accessibility, aberrant histone modification, chromosomal aneuploidy and senescent-like states. This review provides a comprehensive overview of the molecular mechanisms underlying PREMBA, categorized into those that are attributable to known genetic mutations and those with unexplained reasons. Full article

Periodontal disease is a chronic inflammatory condition that destroys tooth-supporting tissues, particularly the alveolar bone and the periodontal ligament, and effective regenerative therapies remain limited. While the role of metabolic–epigenomic crosstalk in determining cell fate is well established, the specific mechanism by which a tricarboxylic acid (TCA) cycle metabolite can modulate chromatin regulation to promote periodontal regeneration remains to be elucidated. The impact of one TCA cycle metabolite, alpha-ketoglutarate (α-KG), was examined in human periodontal ligament fibroblasts cultured under osteogenic induction and profiled by ALP assays, RT-qPCR, analyses of multiple histone modifications, ATAC-seq, and RNA-seq. α-KG increased ALP activity and upregulated genes associated with osteogenesis and the extracellular matrix (ECM). ATAC-seq revealed minimal genome-wide accessibility changes, whereas histone analyses showed reduced H3K27me3, consistent with an epigenetic mechanism that does not require extensive chromatin opening. The RNA-seq identified 14 upregulated α-KG-induced genes, including multiple components of the OGN-OMD-PLAP1/ASPN-ECM2 loci, supporting an osteogenic/ECM transcriptional program. In a mouse periodontal regeneration model, oral administration of α-KG enhanced alveolar bone regeneration and reduced H3K27me3 signals and collagen-rich tissue organization within the periodontal ligament space. These findings identify α-KG as a metabolite-driven epigenetic modulator that alleviates H3K27me3-mediated repression and supports periodontal regeneration. Full article

Adolescence represents a critical window of metabolic plasticity, during which profound hormonal, neurobiological, and physiological remodelling increases susceptibility to nutritional exposures. In parallel with the rising prevalence of obesity, insulin resistance, metabolic syndrome, and non-alcoholic fatty liver disease among young people, there is growing interest in the potential for functional food components to modulate epigenetic pathways that govern metabolic programming. This narrative review synthesises current evidence (2015–2025) from PubMed, Scopus, Web of Science, and Embase to elucidate how diet-derived bioactive compounds influence epigenetic regulation relevant to adipogenesis, appetite control, insulin signalling, and lipid homeostasis during adolescence. Particular emphasis is placed on molecular mechanisms, including DNA methylation changes in genes regulating adipocyte differentiation, hypothalamic neuropeptide expression, and pancreatic β-cell function; histone modifications, such as acetylation and methylation events that remodel chromatin accessibility in metabolic tissues; and modulation of microRNA networks implicated in lipid metabolism, inflammatory signalling, and insulin secretion. Furthermore, the review examines the interplay between diet, the gut microbiota, and the epigenome, highlighting the role of microbially derived short-chain fatty acids (SCFAs) as endogenous histone deacetylase inhibitors and mediators of epigenetic remodelling in adipose tissue. By linking these mechanisms to specific functional food components, including polyphenols, long-chain omega-3 fatty acids, fermentable dietary fibre, and other bioactive molecules, we demonstrate how nutritional signals can counteract maladaptive metabolic trajectories and potentially reduce the intergenerational transmission of metabolic risk. A deeper understanding of these epigenetic effects provides the foundation for developing personalised nutrition strategies aimed at preventing metabolic disorders from emerging during adolescence and beyond. Full article

Background: Vascular calcification (VC) affects up to 90% of patients with end-stage renal disease and increases cardiovascular mortality 3- to 5-fold. Once considered passive mineral deposition, VC is now recognized as an active, toxin-driven process orchestrating vascular smooth muscle cell transdifferentiation, endothelial dysfunction, and matrix remodeling. However, current uremic toxin classifications remain biochemically oriented, providing limited clinical guidance for risk stratification and therapeutic selection. Methods: This comprehensive review reframes uremic toxin-driven VC through an integrated phenotypic lens, synthesizing molecular mechanisms, clinical biomarkers, and therapeutic targets into a unified translational framework. Results: We propose five mechanistic-clinical phenotypes representing distinct biological trajectories of vascular injury. These include (1) inflammatory-oxidative (dominated by indoxyl sulfate, p-cresyl sulfate, NLRP3 inflammasome activation), (2) mineral-metabolic (hyperphosphatemia, FGF23 excess, Klotho deficiency), (3) epigenetic-senescent (histone modifications, microRNA dysregulation, cellular senescence), (4) endocrine cross-talk (vitamin D, PTH, gut-derived metabolites), and (5) integrated toxic continuum (convergence of multiple pathways in advanced disease). A comprehensive biomarker panel spanning inflammatory markers, mineral metabolism parameters, epigenetic indicators, and endocrine-gut metabolites enables phenotypic stratification and therapeutic monitoring. Emerging therapies—including tissue-nonspecific alkaline phosphatase inhibition, ectonucleotide pyrophosphatase/phosphodiesterase 1 enzyme replacement, vitamin K₂ activation, senolytic agents, and SNF472 crystal-growth blockade—are mapped to their optimal phenotypic contexts. Conclusions: This phenotype-oriented paradigm transforms VC from an inevitable complication into a targetable and potentially reversible manifestation of uremic toxicity, establishing a translational foundation for precision-based vascular medicine in chronic kidney disease. The framework enables biomarker-guided patient stratification, rational therapeutic selection, and phenotype-enriched clinical trial design. Full article

Sebaceous glands (SGs) and their specialized subtype, Meibomian glands (MGs), play essential roles in skin and ocular surface homeostasis by producing lipids that maintain barrier integrity and stabilize the tear film. Dysregulation of SG and MG biology contributes to a spectrum of disorders, ranging from benign hyperplasia to sebaceous carcinoma and age-related MG dysfunction. Accumulating evidence highlights the importance of epigenetic regulation, including histone modifications, DNA methylation, and non-coding RNAs (ncRNAs), in controlling SG and MG development, homeostasis, and disease susceptibility. Notably, histone modifiers and ncRNAs modulate acinar differentiation, lipid synthesis, and progenitor cell function. Despite these advances, many epigenetic mechanisms, such as histone lactylation, sumoylation, and phosphorylation, remain underexplored, and several common SG/MG disorders, including chalazion and seborrhea, lack mechanistic studies at the epigenetic level. This review synthesizes current knowledge on SG and MG biology, emphasizing epigenetic regulation, and highlights critical gaps to guide future research aimed at improving the understanding and treatment of SG- and MG-related disorders. Full article

In the Middle East and North Africa (MENA) region, the prevalence of Type 2 Diabetes (T2D) is 17–18%, substantially higher than the ~9–10% reported in Western populations, with some Gulf states approaching 25% in adults. Historically, Arab diets, characterized by high fiber intake from whole grains, legumes, and fermented dairy products, have contrasted markedly with the Western dietary pattern increasingly prevalent among urbanized Arab populations. These nutritional shifts have been associated with changes in gut microbial composition, including lower representation of short-chain fatty acid–producing bacteria and higher abundance of dysbiosis-associated taxa. Concurrently, diet-derived compounds and microbial metabolites have been associated with changes in DNA methylation, histone modifications, and non-coding RNA expression. Epigenome-wide association studies revealed both shared and population-specific methylation signatures in patients with T2D. However, integrated multi-omics studies remain limited in Arab populations, where the disease burden is highest. This review integrates emerging evidence on diet-linked epigenetic alterations, microbiome-associated metabolic pathways, and their intersection in potentially contributing to T2D risk and progression. Given the heterogeneity of T2D across populations, there is a pressing need for culturally contextualized precision medicine frameworks that integrate population-specific diet–microbiome–epigenome dynamics rather than extrapolating findings across populations. Additionally, this review synthesizes evidence that dietary patterns are associated with T2D-relevant pathways through the diet–microbiome–epigenome axis, with emphasis on Arab/MENA populations and Western comparator cohorts. Full article