Search Results (79)

Osteosarcoma (OS), the most common primary bone cancer of mesenchymal origin in children and young adolescents, remains a challenge due to metastasis and resistance to chemotherapy. It displays severe aneuploidy and a high mutation frequency which drive tumor initiation and progression; however, recent studies have highlighted the role of epigenetic modifications as a key driver of OS pathogenesis, independent of genetic mutations. DNA and RNA methylation, histone modifications and non-coding RNAs are among the major epigenetic modifications which can modulate the expression of oncogenes. Abnormal activity of these mechanisms contributes to gene dysregulation, metastasis and immune evasion. Therapeutic targeting against these epigenetic mechanisms, including inhibitors of DNA and RNA methylation as well as regulators of RNA modifications, can enhance tumor suppressor gene activity. In this review, we examine recent studies elucidating the role of epigenetic regulation in OS pathogenesis and discuss emerging drugs or interventions with potential clinical utility. Understanding of tumor- specific epigenetic alterations, coupled with innovative therapeutic strategies and AI-driven biomarker discovery, could pave the way for personalized therapies based on the molecular profile of each tumor and improve the management of patients with OS. Full article

Sporadic colorectal cancer (CRC), the third leading cause of cancer-related death globally, arises through a continuum from normal tissue to adenomas, progressing from low-grade (LGD) to high-grade dysplasia (HGD); yet, the early epigenetic drivers of this transition remain unclear. To investigate these events, we profiled LGD and HGD adenomas using EM-seq, and identified a consensus differential methylation signature (DMS) of 626 regions through two independent bioinformatics pipelines. This signature effectively distinguished LGD from HGD in both tissue and plasma-derived cell-free DNA (cfDNA), highlighting specific methylation patterns. Functional annotation indicated enrichment for regulatory elements associated with transcription factor activity and cell signaling. Applying the DMS to the TCGA CRC dataset revealed three tumor subtypes with increasing hypermethylation and one normal cluster. The most hypermethylated subtype exhibited poor survival, high mutation burden, and disrupted transcriptional networks. While overlapping with classical CpG Island Methylator Phenotype (CIMP) categories, the DMS captured a broader spectrum of methylation alterations. These findings suggest that the DMS captures functionally relevant, antecedent epigenetic alterations in CRC progression, enabling the robust stratification of dysplasia severity and tumor subtypes. This signature holds promise for enhancing preclinical detection and molecular classification, and warrants further evaluation in larger prospective cohorts. Full article

Lung adenocarcinoma (LUAD) is characterized by substantial genetic heterogeneity, making it challenging to identify reliable biomarkers for diagnosis and treatment. Tumor mutational burden (TMB) is widely recognized as a predictive biomarker due to its association with immune response and treatment efficacy. In this study, we take a different approach by treating TMB as a response variable to uncover its genetic drivers using multiomics data. We conducted a thorough evaluation of recent feature selection methods through extensive simulations and identified three top-performing approaches: projection correlation screening (PC-Screen), distance correlation sure independence screening (DC-SIS), and Wasserstein distance-based screening (WD-Screen). Unlike traditional approaches that rely on simple statistical tests or dataset splitting for validation, we adopt a method-based validation strategy, selecting top-ranked features from each method and identifying consistently selected genes across all three. Using The Cancer Genome Atlas (TCGA) dataset, we integrated copy number alteration (CNA), mRNA expression, and DNA methylation data as predictors and applied our selected methods. In the two-platform analysis (mRNA + CNA), we identified 13 key genes, including both previously reported LUAD-associated genes (CCNG1, CKAP2L, HSD17B4, SHROOM1, TIGD6, and TMEM173) and novel candidates (DTWD2, FLJ33630, NME5, NUDT12, PCBD2, REEP5, and SLC22A5). Expanding to a three-platform analysis (mRNA + CNA + methylation) further refined our findings, with PCBD2 and TMEM173 emerging as the robust candidates. These results highlight the complexity of multiomics integration and the need for advanced feature selection techniques to uncover biologically meaningful patterns. Our multiomics strategy and robust selection approach provide insights into the genetic determinants of TMB, offering potential biomarkers for targeted LUAD therapies and demonstrating the power of Wasserstein distance-based feature selection in complex genomic analysis. Full article

Mitochondrial dysfunction is a pivotal driver in the pathogenesis of acute kidney injury (AKI), chronic kidney disease (CKD), and congenital anomalies of the kidney and urinary tract (CAKUT). The kidneys, second only to the heart in mitochondrial density, rely on oxidative phosphorylation to meet the high ATP demands of solute reabsorption and filtration. Disrupted mitochondrial dynamics, such as excessive fission mediated by Drp1, exacerbate tubular apoptosis and inflammation in AKI models like ischemia–reperfusion injury. In CKD, persistent mitochondrial dysfunction drives oxidative stress, fibrosis, and metabolic reprogramming, with epigenetic mechanisms (DNA methylation, histone modifications, non-coding RNAs) regulating genes critical for mitochondrial homeostasis, such as PMPCB and TFAM. Epigenetic dysregulation also impacts mitochondrial–ER crosstalk, influencing calcium signaling and autophagy in renal pathology. Mitophagy, the selective clearance of damaged mitochondria, plays a dual role in kidney disease. While PINK1/Parkin-mediated mitophagy protects against cisplatin-induced AKI by preventing mitochondrial fragmentation and apoptosis, its dysregulation contributes to fibrosis and CKD progression. For instance, macrophage-specific loss of mitophagy regulators like MFN2 amplifies ROS production and fibrotic responses. Conversely, BNIP3/NIX-dependent mitophagy attenuates contrast-induced AKI by suppressing NLRP3 inflammasome activation. In diabetic nephropathy, impaired mitophagy correlates with declining eGFR and interstitial fibrosis, highlighting its diagnostic and therapeutic potential. Emerging therapeutic strategies target mitochondrial dysfunction through antioxidants (e.g., MitoQ, SS-31), mitophagy inducers (e.g., COPT nanoparticles), and mitochondrial transplantation, which mitigates AKI by restoring bioenergetics and modulating inflammatory pathways. Nanotechnology-enhanced drug delivery systems, such as curcumin-loaded nanoparticles, improve renal targeting and reduce oxidative stress. Epigenetic interventions, including PPAR-α agonists and KLF4 modulators, show promise in reversing metabolic reprogramming and fibrosis. These advances underscore mitochondria as central hubs in renal pathophysiology. Tailored interventions—ranging from Drp1 inhibition to mitochondrial transplantation—hold transformative potential to mitigate kidney injury and improve clinical outcomes. Additionally, dietary interventions and novel regulators such as adenogens are emerging as promising strategies to modulate mitochondrial function and attenuate kidney disease progression. Future research should address the gaps in understanding the role of mitophagy in CAKUT and optimize targeted delivery systems for precision therapies. Full article

Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) are dermal-based sarcomas that fall along a spectrum with different rates of local recurrence and metastasis. While AFX is less aggressive and confined to the dermis, PDS invades the subcutis. These tumors are most likely of mesenchymal origin, although they share common mutations with undifferentiated squamous cell carcinoma. Due to the rarity of these tumors, few studies have examined their molecular composition and gene expression. Initial studies, including exome and bulk RNA sequencing, targeted DNA sequencing of gene panels, DNA methylation, and copy number analyses, have identified recurrent UV-induced mutations in TP53, NOTCH, CDKN2A, and the TERT promoter. Recently, the first scRNA-seq dataset in AFX and PDS identified COL6A3 as a novel biomarker. In this review, we synthesize the above datasets and discuss our current understanding of the molecular drivers and prognostic biomarkers in these tumors. Full article

Transposable elements (TEs) are major drivers of plant genome plasticity, but the immediate molecular consequences of new TE insertions remain poorly understood. In this study, we generated a wild-type Arabidopsis thaliana population with novel insertions of ONSEN retrotransposon to investigate early epigenomic and transcriptomic changes using whole-genome and cDNA nanopore sequencing. We found that novel ONSEN insertions were distributed non-randomly, with a strong preference for genic regions, particularly in chromatin enriched for H2A.Z, H3K27me3, and H3K4me2. Most full-length ONSEN insertions within genes were rapidly recognized and spliced out as new introns (intronization), thereby mitigating potential deleterious effects on transcript isoforms. In some cases, ONSEN insertions provided alternative transcription start or termination sites, generating novel transcript isoforms. Genome-wide methylation analysis revealed that new ONSEN copies were efficiently and precisely targeted by DNA methylation. Independently on the location of the original ONSEN element, the euchromatic and heterochromatic insertions display distinct methylation signatures, reflecting the action of different epigenetic pathways. In conclusion, our results demonstrate that DNA methylation and alternative splicing are effective control mechanisms safeguarding the plant genome and transcriptome integrity after retrotransposition burst. Full article

Male-factor infertility accounts for nearly half of all infertility cases, and mounting evidence points to oxidative stress as a pivotal driver of sperm dysfunction, genetic instability, and epigenetic dysregulation. In particular, the oxidative DNA lesion 8-hydroxy-2′-deoxyguanosine (8-OHdG) has emerged as a central mediator at the interface of DNA damage and epigenetic regulation. We discuss how this lesion can disrupt key epigenetic mechanisms such as DNA methylation, histone modifications, and small non-coding RNAs, thereby influencing fertilization outcomes, embryo development, and offspring health. We propose that the interplay between oxidative DNA damage and epigenetic reprogramming is further exacerbated by aging in both the paternal and maternal germlines, creating a “perfect storm” that increases the risk of heritable (epi)mutations. The consequences of unresolved oxidative lesions can thus persist beyond fertilization, contributing to transgenerational health risks. Finally, we explore the promise and potential pitfalls of antioxidant therapy as a strategy to mitigate sperm oxidative damage. While antioxidant supplementation may hold significant therapeutic value for men with subfertility experiencing elevated oxidative stress, a careful, personalized approach is essential to avoid reductive stress and unintended epigenetic disruptions. Recognizing the dual role of oxidative stress in shaping both the genome and the epigenome underscores the need for integrating redox biology into reproductive medicine, with the aim of improving fertility treatments and safeguarding the health of future generations. Full article

DNA methylation is crucial in gene expression regulation and tissue differentiation in livestock. However, genome-wide methylation patterns among tissues remain underexplored in cattle, one of the world’s most important farm animals. This study investigates sex- and tissue-specific DNA methylation in cattle using CpG site methylation data generated by an Infinium DNA Methylation array (HorvathMammalMethyl-Chip40) across seven tissues. Our analysis revealed significant tissue-specific methylation differences, with reproductive tissues/cells, such as the sperm, exhibiting distinct profiles compared to somatic tissues like hair and blood. Principal component analysis (PCA) highlighted tissue differentiation as the primary driver of methylation variability. We also identified 222 CpG sites with significant sex-based methylation differences, particularly on the X chromosome, suggesting the potential epigenetic regulation of sex-specific traits. The Gene Ontology (GO) enrichment analysis indicated that these methylation patterns may influence biological processes such as epithelial cell proliferation and blood vessel remodeling. Overall, this study provides important insights into sex- and tissue-specific epigenetic regulation in cattle, with implications for improving livestock breeding strategies through integrating epigenetic data. Full article

DNA methylation, a cornerstone of epigenetic regulation, governs critical biological processes including transcriptional modulation, genomic imprinting, and transposon suppression through chromatin architecture remodeling. Recent advances have revealed that aberrant methylation patterns—characterized by spatial-temporal dysregulation and stochastic molecular noise—serve as key drivers of diverse pathological conditions, from oncogenesis to neurodegenerative disorders. However, the field faces dual challenges: (1) current understanding remains fragmented due to the inherent spatiotemporal heterogeneity of methylation landscapes across tissues and developmental stages, and (2) mechanistic insights into non-canonical methylation pathways (particularly 6mA) in non-mammalian systems are conspicuously underdeveloped. This review systematically synthesizes the evolutionary-conserved versus species-specific features of 5-methylcytosine (5mC) and N6-methyladenine (6mA) regulatory networks across three biological kingdoms. Through comparative analysis of methylation/demethylation enzymatic cascades (DNMTs/TETs in mammals, CMTs/ROS1 in plants, and DIM-2/DNMTA in fungi), we propose a unified framework for targeting methylation-associated diseases through precision epigenome editing, while identifying critical knowledge gaps in fungal methylome engineering that demand urgent investigation. Full article

Hepatoblastoma (HB) is the most common malignant liver tumor in children under five years of age. Although globally rare, it accounts for a large proportion of liver cancer in children and has poor survival rates in high-risk and metastatic cases. This review discusses the molecular mechanisms, diagnostic methods, and therapeutic strategies of HB. Mutations in the CTNNB1 gene and the activation of the Wnt/β-catenin pathway are essential genetic factors. Furthermore, genetic syndromes like Beckwith–Wiedemann syndrome (BWS) and Familial Adenomatous Polyposis (FAP) considerably heighten the risk of associated conditions. Additionally, epigenetic mechanisms, such as DNA methylation and the influence of non-coding RNAs (ncRNAs), are pivotal drivers of tumor development. Diagnostics include serum biomarkers, immunohistochemistry (IHC), and imaging techniques. Standard treatments are chemotherapy, surgical resection, and liver transplantation (LT). Emerging therapies like immunotherapy and targeted treatments offer hope against chemotherapy resistance. Future research will prioritize personalized medicine, novel biomarkers, and molecular-targeted therapies to improve survival outcomes. Full article

Background/Objectives: Genetics and epigenetics play an important role in the pathogenesis of cutaneous melanoma. The majority of cases harbor mutations in genes associated with the MAPK signaling pathway, i.e., BRAF, NRAS, or NF1. The remaining neoplasms, often located on acral sites, are condensed as the triple-wildtype subtype and are characterized by other molecular drivers. This study aimed to elucidate genetic and epigenetic differences within cutaneous melanoma and to compare it with melanocytic nevi. Methods: DNA was extracted from archived tissue samples of cutaneous melanoma (n = 19), melanocytic nevi (n = 11), and skin controls (n = 11) and subsequently analyzed by massive parallel (next generation) gene panel sequencing and genome-wide DNA methylation array analysis. The sample size was increased by including repository data from an external study. Results: There were major differences in the genomic landscape of MAPK-altered and triple-wildtype cutaneous melanoma, the latter presenting with a lower number of mutations, a different pattern of copy number variants, and a low frequency of TERT promoter mutations. Dimensional reduction of DNA methylation array analysis clearly separated cutaneous melanoma from melanocytic nevi but revealed no major differences between classical cutaneous melanoma and the triple-wildtype cases. However, it identified a possible biological subgroup characterized by intermediately methylated CpGs. Conclusions: Dimensional reduction of methylation array data is a useful tool for the analysis of melanocytic tumors to differentiate between malignant and benign lesions and may be able to identify biologically distinct subtypes of cutaneous melanoma. Full article

Lung cancer remains the leading cause of cancer-related deaths worldwide, driven by its complexity and the heterogeneity of its subtypes, which influence pathogenesis, tumor microenvironment, and genetic alterations. We developed a novel weighted gene regulatory network reconstruction method based on maximum entropy and Markov chain entropy principles, which integrates gene expression and DNA methylation data to generate biologically informed networks. Applied to LUAD and LUSC datasets, we define a network methylation index to determine whether gene methylation acts as oncogenic or tumor-suppressive. By revealing a stable core set of pathogenic genes, we identify not only genes with significant expression changes, such as CD74 and HGF, but also pathogenic genes with stable expression, such as BRAF and KDM6A. Additionally, we uncover potential driver genes, such as CORO2B and C20orf194, associated with disease stage, gender, and smoking status. This method offers a more comprehensive understanding of NSCLC mechanisms, paving the way for improved therapeutic strategies. Full article

Background/Objectives: Glioblastoma is the most common malignant primary brain tumor, characterized by necrosis, uncontrolled proliferation, infiltration, angiogenesis, apoptosis resistance, and genomic instability. Epigenetic modifiers hold promise as adjuvant therapies for gliomas, with synergistic combinations being explored to enhance efficacy and reduce toxicity. This study aimed to evaluate the effects of single or combined treatments with various anticancer drugs (Carboplatin, Paclitaxel, Avastin), natural compounds (Quercetin), and epigenetic modulators (suberoylanilide hydroxamic acid and 5-Azacytidine) on the expression of some long noncoding RNAs and methylation drivers or some functional features in the U87-MG cell line. Methods: Treated and untreated U87-MG cells were used for the evaluation of drug-induced cytotoxicity, apoptotic events, and distribution in cell cycle phases, detection of cytokine release, and assessment of gene expression and global methylation. Results: Cytotoxicity assays led to the selection of drug concentrations to be used in further experiments. Expression analysis revealed distinct downregulation of nearly all investigated genes and long noncoding RNAs following treatments. All treatments resulted in a higher percentage of global methylation compared to untreated controls. All treatments effectively increased levels of apoptosis, while the epigenetic modulators exhibited a lower proliferation profile, with combined treatments showing elevated values of cell lysis. Conclusions: The results indicate a link between Carboplatin and Avastin treatments and DNA methylation mechanisms involving EZH2, DNMT3A, and DNMT3B, with Avastin’s direct impact on these enzymes warranting further study. This research underscores the promise of platinum-based therapies combined with epigenetic drugs to reactivate silenced tumor suppressor genes and optimize methylation profiles. Full article

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic cancers characterized by hyperproliferation of the myeloid lineages. These clonal marrow disorders are extremely rare in pediatric patients. MPN is reported to occur 100 times more frequently in adults, and thus research is primarily focused on this patient group. At present, modern diagnostic techniques, primarily genetic, facilitate the identification of the biology of these diseases. The key genes are JAK2, MPL, and CALR, namely, driver mutations, which are present in approximately 90% of patients with suspected MPN. Moreover, there are more than 20 other mutations that affect the development of these hematological malignancies, as evidenced by a review of the literature. The pathogenic mechanism of MPNs is characterized by the dysregulation of the JAK/STAT signaling pathway (JAK2, MPL, CALR), DNA methylation (TET2, DNMT3A, IDH1/2), chromatin structure (ASXL1, EZH2), and splicing (SF3B1, U2AF2, SRSF2). Although rare, myeloproliferative neoplasms can involve young patients and pose unique challenges for clinicians in diagnosis and therapy. The paper aims to review the biological markers of MPNs in pediatric populations—a particular group of patients that has been poorly studied due to the low frequency of MPN diagnosis. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by its aggressive progression and dismal prognosis. Advances in epigenetic profiling, specifically DNA methylation analysis, have significantly deepened our understanding of PDAC pathogenesis. This review synthesizes findings from recent genome-wide DNA methylation studies, which have delineated a complex DNA methylation landscape differentiating between normal and cancerous pancreatic tissues, as well as across various stages and molecular subtypes of PDAC. These studies identified specific differentially methylated regions (DMRs) that not only enhance our grasp of the epigenetic drivers of PDAC but also offer potential biomarkers for early diagnosis and prognosis, enabling the customization of therapeutic approaches. The review further explores how DNA methylation profiling could facilitate the development of subtype-tailored therapies, potentially improving treatment outcomes based on precise molecular characterizations. Overall, leveraging DNA methylation alterations as functional biomarkers holds promise for advancing our understanding of disease progression and refining PDAC management strategies, which could lead to improved patient outcomes and a deeper comprehension of the disease’s underlying biological mechanisms. Full article