Search Results (3,290)

Background: Regular endurance training induces physiological changes in cardiac structure and function. The precise epigenetic mechanisms by which cardiovascular adaptations are mediated are still unclear. This review seeks to clarify the role of epigenetic regulation in exercise-induced cardiovascular adaptation. Methods: This systematic review was conducted in accordance with the PRISMA guidelines up to 30 April 2025, using the databases PubMed, VHL, and LILACS Plus. Studies were included if they focused on microRNA expression and DNA methylation in individuals with cardiovascular disease who underwent endurance training. Results: Six articles, including 384 participants with heart failure, coronary artery disease, and hypertension, were included in the final analysis. Changes in DNA methylation and microRNA expression of specific genes involved in cardiovascular structural and functional adaptation were observed. Significant improvements were found in body composition, VO2peak, systolic and diastolic blood pressure, and left ventricular function and structure. Conclusions: Endurance training has a positive impact on epigenetic mechanisms related to cardiovascular structural and functional adaptation. A clear causal link between epigenetic modifications and clinical outcomes remains to be established. Full article

Starvation in horses presents critical welfare, economic, and management challenges with underlying molecular mechanisms of metabolic modification and recovery left poorly defined. Prolonged caloric deprivation induces significant systemic shifts in carbohydrate, protein, and lipid metabolism, reflected in coordinated changes in tissue-specific gene expression. This review synthesizes current knowledge on equine metabolic responses to starvation, emphasizing pathways found through RNA sequencing (RNA-seq) and real-time quantitative polymerase chain reaction (RT-qPCR) studies. Molecular investigations using RNA-seq and RT-qPCR have provided insight into transcriptional reprogramming during starvation and subsequent refeeding. Shifts in gene expression reflect the metabolic transition from carbohydrate dependence to lipid use, suppression of anabolic signaling, and activation of proteolytic pathways. However, interpretation of these data requires caution, as factors such as post-mortem interval, tissue handling, and euthanasia methods particularly the use of sodium barbiturates can influence transcript stability and abundance, potentially confounding results. The literature shows that starvation-induced molecular changes are not uniform across tissues, with skeletal muscle, liver, and adipose tissue showing distinct transcriptional signatures and variable recovery patterns during refeeding. Cross-species comparisons with hibernation, caloric restriction, and cachexia models provide context for understanding these changes, though equine-specific studies remain limited. Identified gaps include the scarcity of longitudinal data, inconsistent tissue sampling protocols, and lack of standardized reference genes for transcriptomic analyses in horses. Addressing these limitations will improve the accuracy of molecular evaluations and enhance our ability to predict recovery trajectories. A more comprehensive understanding of systemic and tissue-specific responses to starvation will inform evidence-based rehabilitation strategies, reduce the risk of refeeding syndrome, and improve survival and welfare outcomes for affected horses. Full article

The submandibular glands (SMGs), along with the parotid and sublingual glands, generate the majority of saliva and play critical roles in maintaining oral and systemic health. Despite their physiological importance, long-term therapeutic options for salivary gland dysfunction remain limited, highlighting the need for a deeper molecular understanding of SMG biology, particularly in humans. To address this knowledge gap, we have performed transcriptomic- and epigenomic-based analyses and molecular characterization of the human SMG. Our integrated analysis of multiorgan RNA-sequencing datasets has identified an SMG-enriched gene expression signature comprising 289 protein-coding and 75 long non-coding RNA (lncRNA) genes that include both known regulators of salivary gland function and several novel candidates ripe for future exploration. To complement these transcriptomic studies, we have generated chromatin immunoprecipitation sequencing (ChIP-seq) datasets of key histone modifications on human SMGs. Our epigenomic analyses have allowed us to identify genome-wide enhancers and super-enhancers that are likely to drive genes and regulatory pathways that are important in human SMG biology. Finally, comparative analysis with mouse and human SMG and other tissue datasets reveals evolutionary conserved gene and regulatory networks, underscoring fundamental mechanisms of salivary gland biology. Collectively, this study offers a valuable knowledge-based resource that can facilitate targeted research on salivary gland dysfunction in human patients. Full article

RNA-based therapeutics offer transformative potential for treating devastating diseases. However, current RNA delivery technologies face significant hurdles, including inefficient tissue targeting, insufficient selectivity, and severe side effects, leading to the termination of many clinical trials. This review critically assesses the landscape of RNA-derived medicines, examining world-renowned mRNA vaccines (Spikevax, BNT162b2/Comirnaty) and RNA-based therapeutics like Miravirsen (anti-miR-122). It details the composition and clinical trial results of numerous modified short RNA drugs (e.g., siRNAs, miRNA mimetics/inhibitors) targeting various conditions. Prospects for RNA-based medicines are analysed for diseases with substantial societal impact, such as cancer, autoimmune disorders, and infectious diseases, with a focus on evolving delivery methods, including lipid nanoparticles, viral vectors, and exosomes. RNA-mediated macrophage reprogramming emerges as a promising strategy, potentially enhancing both delivery and clinical efficacy. This review highlights that while approved RNA therapies primarily target rare diseases due to delivery limitations, novel approaches in RNA modification, targeted delivery systems, and enhanced understanding of molecular mechanisms are crucial for expanding their application to prevalent diseases and unlocking their full therapeutic potential. Full article

Long noncoding RNAs (lncRNAs) are transcripts generated by polymerase II, therefore subject to 5′ capping and 3′ polyadenylation, categorized as such when they are at least 200 nt in size and lack coding function. The lncRNAs were initially interpreted as spurious transcription products, but over the last two decades an increasing amount of evidence has accumulated for regulatory functions. They are found in all taxonomic groups, including bacteria, archaea, fungi, animals and plants. In fungi, global analyses anticipate their presence in higher numbers than initially expected considering the simplicity of these organisms. Except for the numerous studies performed in budding and fission yeast, relatively few lncRNAs have been investigated in sufficient detail in the rest of the fungi, but their number has increased steadily in recent years. The lncRNAs can be transcribed from intergenic regions or coincide totally or partially with protein-coding genes, in which case they are most frequently antisense transcripts. Their regulatory functions can be performed by a wide variety of mechanisms, both in cis on neighboring genes and in trans on distant genes or on proteins. Among the most frequent mechanisms are interference on the transcription of neighboring genes and generation of epigenetic modifications in the environment of target genes. Here, we review the most representative cases of global analyses of the presence of lncRNAs in fungal transcriptomes and describe the lncRNAs that have received more detailed attention. Full article

Background/Objectives: Gestational weight gain (GWG) is a crucial factor influencing mother and fetal health, as high GWG is associated with adverse pregnancy outcomes and an increased long-term risk of obesity and metabolic issues in the children. In addition to controlling weight, maternal physical activity (PA) during pregnancy may influence fetal development through potential epigenetic mechanisms, including histone modifications, DNA methylation, and the production of non-coding RNA. Methods: This narrative review synthesizes evidence from randomized controlled trials (RCTs; n = 11, 3654 participants) investigating the impact of aerobic PA on GWG, while also highlighting emerging, primarily indirect findings on maternal–fetal epigenetic programming. Results: The majority of RCTs found that supervised PA interventions, especially when paired with nutritional counseling, decreased both the incidence of excessive GWG and total GWG. Enhancements in lipid metabolism, adipokine profiles, and maternal insulin sensitivity point to likely biochemical mechanisms that connect PA to epigenetic modification of fetal metabolic genes (e.g., IGF2, PGC-1α, LEP). Animal and observational studies suggest that maternal activity may influence offspring epigenetic pathways related to obesity and cardiometabolic conditions, although direct human evidence is limited. Conclusions: In addition to potentially changing gene–environment interactions throughout generations, prenatal PA is a low-cost, safe method of improving maternal and newborn health. Future RCTs ought to incorporate molecular endpoints to elucidate the epigenetic processes by which maternal exercise may provide long-term health benefits. Full article

Exercise plays a crucial role in promoting overall health by activating molecular pathways that contribute to the prevention and management of chronic diseases, slowing epigenetic aging, improving body composition, and reducing the risk of obesity. In skeletal muscle, these benefits are largely mediated by exercise-induced transcriptional and epigenetic responses. Recent advances in epigenetics have intensified interest in understanding how physical activity influences long-term health and body composition at the molecular level. Epigenetic modifications, which regulate gene expression without altering the DNA sequence, are key mechanisms in this process. Emerging research has provided deeper insights into the processes such as DNA methylation, histone modification, and non-coding RNAs, and their connection to exercise. While numerous studies have demonstrated the influence of exercise on the epigenome, fewer have directly examined how these molecular changes relate to alterations in fat mass, lean body mass, and other components of body composition. This comprehensive review synthesizes the current evidence on the interplay between exercise, epigenetic regulation, and body composition, with a focus on adolescents and adults. We highlight key genes involved in metabolism, fat storage, muscle development, and epigenetic aging, and explore how their regulation may contribute to individual variability in exercise response. Understanding these molecular pathways may provide valuable insights for optimizing exercise interventions aimed at improving health outcomes across the lifespan. Full article

Cancer-associated fibroblasts (CAFs) are a key constituent of the tumor microenvironment. CAFs may affect the development of tumor cells. The critical role of CAFs in the tumor microenvironment is linked to their epigenetic modifications, as a stable yet reversible regulation of cellular phenotypes. Current evidence indicates that their formation and function are closely linked to epigenetic mechanisms. Existing research indicates that the epigenetic alteration abnormalities are triggered by metabolic cues and stabilize the acquired phenotype of CAFs. This process is associated with transcriptional changes and patient outcomes in various tumors, providing a biological rationale and translational potential for reprogramming CAFs. Understanding of epigenetic modifications in CAFs remain insufficient, while DNA methylation in CAFs can alter CAF states through multiple pathways and thereby influence tumor progression. It is necessary to investigate the unique, identifiable epigenetic signatures of CAF. As an epigenetic reader couple histone acetylation to high-output oncogenic transcription; meanwhile, noncoding RNAs modulate CAF formation and therapeutic responses via bidirectional crosstalk between tumor cells and stroma. The interactions between different epigenetic modifications and their underlying regulatory logic may play a crucial role in developing new therapeutic strategies. This review focuses on the roles of DNA methylation, histone acetylation, and enhancer reprogramming in CAFs. Full article

Background/Objectives: Glioblastoma (GBM) is an aggressive primary brain tumor with limited therapeutic options despite multimodal treatment. Small interfering RNA (siRNA)-based therapeutics can silence tumor-promoting genes, but achieving efficient and tumor-specific delivery remains challenging. Lipid nanoparticles (LNPs) are promising siRNA carriers; however, conventional antibody conjugation can impair antigen recognition and complicate manufacturing. This study aimed to establish a modular Fc-binding peptide (FcBP)-mediated post-insertion strategy to enable PD-L1-targeted delivery of VEGF-siRNA via LNPs for GBM therapy. Methods: Preformed VEGF-siRNA-loaded LNPs were functionalized with FcBP–lipid conjugates, enabling non-covalent anchoring of anti-PD-L1 antibodies through Fc interactions. Particle characteristics were analyzed using dynamic light scattering and encapsulation efficiency assays. Targeted cellular uptake and VEGF gene silencing were evaluated in PD-L1-positive GL261 glioma cells. Anti-tumor efficacy was assessed in a subcutaneous GL261 tumor model following repeated intratumoral administration using tumor volume and bioluminescence imaging as endpoints. Results: FcBP post-insertion preserved LNP particle size (125.2 ± 1.3 nm), polydispersity, zeta potential, and siRNA encapsulation efficiency. Anti-PD-L1–FcBP-LNPs significantly enhanced cellular uptake (by ~50-fold) and VEGF silencing in PD-L1-expressing GL261 cells compared to controls. In vivo, targeted LNPs reduced tumor volume by 65% and markedly suppressed bioluminescence signals without inducing weight loss. Final tumor weight was reduced by 63% in the anti-PD-L1–FcBP–LNP group (656.9 ± 125.4 mg) compared to the VEGF-siRNA LNP group (1794.1 ± 103.7 mg). The FcBP-modified LNPs maintained antibody orientation and binding activity, enabling rapid functionalization with targeting antibodies. Conclusions: The FcBP-mediated post-insertion strategy enables site-specific, modular antibody functionalization of LNPs without compromising physicochemical integrity or antibody recognition. PD-L1-targeted VEGF-siRNA delivery demonstrated potent, selective anti-tumor effects in GBM murine models. This platform offers a versatile approach for targeted nucleic acid therapeutics and holds translational potential for treating GBM. Full article

The methylation of CpG sites with 5mC mark is a dynamic epigenetic modification. However, the relationship between the methylation and the surrounding genomic sequence context remains poorly explored. Investigation of the allele methylation provides an opportunity to decipher the interplay between differences in the primary DNA sequence and epigenetic variation. Here, we performed high-coverage long-read whole-genome direct DNA sequencing of one individual using Oxford Nanopore technology. We also used Illumina whole-genome sequencing of the parental genomes in order to identify allele-specific methylation sites with a trio-binning approach. We have compared the results of the haplotype-specific methylation detection and revealed that trio binning outperformed other approaches that do not take into account parental information. Also, we analysed the cis-regulatory effects of the genomic variations for influence on CpG methylation. To this end, we have used available Deep Learning models trained on the primary DNA sequence to score the cis-regulatory potential of the genomic loci. We evaluated the functional role of the allele-specific epigenetic changes with respect to gene expression using long-read Nanopore RNA sequencing. Our analysis revealed that the frequency of SNVs near allele-specific methylation positions is approximately four times higher compared to the biallelic methylation positions. In addition, we identified that allele-specific methylation sites are more conserved and enriched at the chromatin states corresponding to bivalent promoters and enhancers. Together, these findings suggest that significant impact on methylation can be encoded in the DNA sequence context. In order to elucidate the effect of the SNVs around sites of allele-specific methylation, we applied the Deep Learning model for detection of the cis-regulatory modules and estimated the impact that a genomic variant brings with respect to changes to the regulatory activity of a DNA loci. We revealed higher cis-regulatory impact variants near differentially methylated sites that we further coupled with transcriptomic long-read sequencing results. Our investigation also highlights technical aspects of allele methylation analysis and the impact of sequencing coverage on the accuracy of genomic phasing. In particular, increasing coverage above 30X does not lead to a significant improvement in allele-specific methylation discovery, and only the addition of trio binning information significantly improves phasing. We investigated genomic variation in a single human individual and coupled computational discovery of cis-regulatory modules with allele-specific methylation (ASM) profiling. In this proof-of-concept analysis, we observed that SNPs located near methylated CpG sites on the same haplotype were enriched for sequence features suggestive of high-impact regulatory potential. This finding—derived from one deeply sequenced genome—illustrates how phased genetic and epigenetic data analyses can jointly put forward a hypotheses about the involvement of regulatory protein machinery in shaping allele-specific epigenetic states. Our investigation provides a methodological framework and candidate loci for future studies of genomic imprinting and cis-mediated epigenetic regulation in humans. Full article

Plants have evolved a complex, multilayered immune system that integrates molecular recognition, signaling pathways, epigenetic regulation, and small RNA-mediated control. Recent studies have shown that DNA-level regulatory mechanisms, such as RNA-directed DNA methylation (RdDM), histone modifications, and chromatin remodeling, are critical for modulating immune gene expression, allowing for rapid and accurate pathogen-defense responses. The epigenetic landscape not only maintains immunological homeostasis but also promotes stress-responsive transcription via stable chromatin modifications. These changes contribute to immunological priming, a process in which earlier exposure to pathogens or abiotic stress causes a heightened state of preparedness for future encounters. Small RNAs, including siRNAs, miRNAs, and phasiRNAs, are essential for gene silencing before and after transcription, fine-tuning immune responses, and inhibiting negative regulators. These RNA molecules interact closely with chromatin features, influencing histone acetylation/methylation (e.g., H3K4me3, H3K27me3) and guiding DNA methylation patterns. Epigenetically encoded immune memory can be stable across multiple generations, resulting in the transgenerational inheritance of stress resilience. Such memory effects have been observed in rice, tomato, maize, and Arabidopsis. This review summarizes new findings on short RNA biology, chromatin-level immunological control, and epigenetic memory in plant defense. Emerging technologies, such as ATAC-seq (Assay for Transposase-Accessible Chromatin using Sequencing), ChIP-seq (Chromatin Immunoprecipitation followed by Sequencing), bisulfite sequencing, and CRISPR/dCas9-based epigenome editing, are helping researchers comprehend these pathways. These developments hold an opportunity for establishing epigenetic breeding strategies that target the production of non-GMO, stress-resistant crops for sustainable agriculture. Full article

Background: The precise role of RNA modification in post-traumatic stress disorder (PTSD) remains incompletely understood. This study aims to elucidate the effects of five common RNA modifications in PTSD, specifically m⁶A, m⁵C, m¹A, m⁷G, and ψ. Methods: We extracted data from the GEO repository to conduct a series of bioinformatics analyses. These included differential analysis to identify key regulators of five common RNA modifications, model construction using random forest (RF), least absolute shrinkage and selection operator (LASSO), and nomogram techniques, as well as consensus clustering of RNA modification subtypes. Furthermore, GO enrichment analysis was performed on DEGs associated with various RNA modification patterns. Immune cell infiltration was assessed using PCA and ssGSEA. RT-qPCR was performed to validate RNA modification-related genes (RMGs). Results: Twenty-one differentially expressed RMGs were identified. LASSO and RF intersection yielded eight signature genes (YTHDC1, IGFBP1, IGF2BP1, ALKBH5, NSUN4, TET2, TET3, WDR4) that robustly diagnosed PTSD (AUC = 0.804). Furthermore, these feature genes were validated using RT-qPCR, which was basically consistent with the results of bioinformatics analysis. Consensus clustering analysis may reveal two distinguishable subtypes: clusterA marked by high immunoinflammation, and clusterB characterized by high-neuroendocrine dysregulation. Conclusions: RMGs may play a crucial role in the pathogenesis of PTSD. Analyzing RNA modification patterns could offer potential diagnostic markers and help to guide immunotherapeutic approaches or neurotransmitter system interventions for PTSD in the future. Full article

MicroRNAs (miRNAs) are small non-coding RNAs that play pivotal roles in post-transcriptional gene regulation, influencing development, differentiation, and disease pathogenesis. Since their discovery in 1993, miRNAs have been recognized for their evolutionary conservation and pleiotropic effects, with the 2024 Nobel Prize underscoring their significance in post-transcriptional regulation via the RNA interference (RNAi) pathway. This review synthesizes the complete life cycle of miRNAs—from transcription and processing to function and decay—emphasizing regulatory mechanisms and their implications in human diseases, particularly cancer. We discuss how epitranscriptomic modifications influence miRNA biogenesis and activity, explore their nuclear and mitochondrial functions, and address emerging challenges in miRNA-based therapeutics, including the expanding small RNA landscape such as tRNA-derived small RNAs (tsRNAs), and Argonaute (AGO)-independent activities. Despite hurdles such as modest multi-target effects, off-target interactions, and delivery challenges, miRNAs remain promising as both biomarkers and therapeutic agents, underscoring the need for sustained research to bridge preclinical insights with clinical applications. Full article

The rising global prevalence of inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis, is paralleled by an increased risk of colitis-associated colorectal cancer. Persistent intestinal inflammation promotes genetic instability and epigenetic reprogramming within epithelial and immune cells, driving the multistep transition from inflammation to neoplasia. This review integrates human and preclinical model evidence with literature mining and bioinformatic analyses of genetic, epigenetic, and ncRNA data to dissect molecular mechanisms driving colitis-associated colorectal cancer from chronic inflammation. We highlight how pro-inflammatory cytokines (e.g., TNF-α, IL-6), oxidative stress, and microbial dysbiosis converge on key transcriptional regulators such as NF-κB and STAT3, inducing DNA methylation and histone modifications (e.g., H3K27me3); altering chromatin dynamics, gene expression, and non-coding RNA networks (e.g., miR-21, MALAT1, CRNDE); ultimately reshaping pathways involved in proliferation, apoptosis, and immune evasion. This review updates new potential associations of entities with these diseases, in their networks of interaction, summarizing major aspects of genetic and chromatin-level regulatory mechanisms in inflammatory bowel disease and colorectal cancer, and emphasizing how these interactions drive the inflammatory-to-neoplastic transition. By underscoring the reversibility of epigenetic changes, we explore their translational potential in early detection, surveillance, and precision epigenetic therapy. Understanding the interplay between genetic mutations and chromatin remodeling provides a roadmap for improving diagnostics and personalized treatments in inflammatory bowel disease-associated colorectal carcinogenesis. Full article

Mitochondria are crucial for a wide range of cellular processes. One of the most important is innate immunity regulation. Apart from functioning as a signaling hub in immune reactions, mitochondrial nucleic acids can themselves act as damage-associated molecular patterns (DAMPs) to participate in immune processes directly. This review synthesizes the current understanding of mitochondrial RNA (mtRNA) biology and its link to immune activation through aberrant accumulation. We focus on its origin through bidirectional mitochondrial transcription and metabolism, encompassing maturation (cleavage, polyadenylation, modification) and degradation. Dysregulation of mtRNA metabolism leads to mt-dsRNA (mitochondrial double-stranded RNA) accumulation, which escapes mitochondria via specific channels into the cytosol and serves as DAMPs to trigger an immune response. We discuss the critical roles of key regulatory factors, including PNPT1 (PNPase, Polyribonucleotide Nucleotidyltrans ferase 1), in controlling mt-dsRNA levels and preventing inappropriate immune activation. Finally, we review the implications of mt-dsRNA-driven inflammation in human diseases, including autoimmune disorders, cellular senescence, and viral infection pathologies, highlighting unresolved questions regarding mt-dsRNA release mechanisms. Full article