Search Results (445)

The innate immune system protects against infection and cellular damage by recognizing conserved pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Emerging evidence suggests that aberrant epigenetic modifications—such as altered DNA methylation and histone marks—can serve as immunogenic signals that activate pattern recognition receptor (PRR)-mediated immune surveillance. This review explores the concept that epigenetic marks may function as DAMPs or even mimic PAMPs. I highlight how unmethylated CpG motifs, which are typically suppressed using host methylation, are recognized as foreign via Toll-like receptor 9 (TLR9). I also examine how cytosolic DNA sensors, including cGAS, detect mislocalized or hypomethylated self-DNA resulting from genomic instability. In addition, I discuss how extracellular histones and nucleosomes released during cell death or stress can act as DAMPs that engage TLRs and activate inflammasomes. In the context of cancer, I review how epigenetic dysregulation can induce a “viral mimicry” state, where reactivation of endogenous retroelements produces double-stranded RNA sensed by RIG-I and MDA5, triggering type I interferon responses. Finally, I address open questions and future directions, including how immune recognition of epigenetic alterations might be leveraged for cancer immunotherapy or regulated to prevent autoimmunity. By integrating recent findings, this review underscores the emerging concept of the epigenome as a target of innate immune recognition, bridging the fields of immunology, epigenetics, and cancer biology. Full article

Uniparental disomies (UPDs) are among the causes of imprinting disorders. Specific phenotypes of most causative UPDs have been described. Here, we describe the case of a 2-year-old female patient who presented a syndromic phenotype. Chromosomal microarray analysis revealed UPD of the whole chromosome 16. Microsatellite analysis demonstrated paternal origin of the UPD and its isodisomic pattern (UPiD (16) pat). Mosaic trisomy 16 was not detected using the FISH method. Whole-exome sequencing revealed no pathogenetic genetic variants sufficient to explain the syndromic phenotype nor unmasked pathogenic recessive genetic variants on chromosome 16. Whole-genome trio DNA sequencing revealed no additional candidate pathogenic genetic variants to those detected by whole-exome sequencing, including miRNAs and lncRNAs. Imprinting disorders at 6q24.2, 7p12.2, 7q32.2, 11p15.5, 14q32.2, 15q11.2, and 20q13.32, as well as multilocus imprinting disturbances (MLIDs), were excluded by Methylation-Specific Multiplex Ligation-Dependent Probe Amplification (MS-MLPA). At the same time, we detected abnormal hypermethylation of the ZNF597 transcription start site differentially methylated region (ZNF597:TSS-DMR), accompanied by hypomethylation of the neighbouring ZNF597:3′ DMR. Both DMRs were normally imprinted, and the DNA alterations in our patient with UPD (16) pat are opposite to those previously described for maternal uniparental disomy (UPD (16) mat). To date, several cases of UPD (16) pat have been reported. Our case report describes the syndromic phenotype of a patient with paternal uniparental disomy of chromosome 16 in contrast to the previously described patients with a normal phenotype or with abnormal phenotypes caused by acquired homozygosity of pathogenic variants at autosomal recessive genes located on this chromosome. Reporting such observations will help systematize data on the phenotypes of imprinting disorders on chromosome 16. Full article

Background: Borderline Personality Disorder (BPD) is a complex psychiatric condition with multifactorial origins, with a high proportion of patients reporting early trauma. Stressors such as adverse childhood experiences (ACEs) can shape the epigenetic landscape including DNA methylation (DNAm) and act on gene expression. DNAm is increasingly being investigated as a molecular link between environmental exposures such as ACE and psychiatric outcomes. Differential DNAm of the gene PR domain zinc finger protein 8 (PRDM8), a histone methyltransferase, has recently been reported to be sensitive to early life trauma. Its role in BPD, especially in the context of ACE, remains to be elucidated. Methods: This study investigated DNAm patterns of PRDM8 in peripheral blood and saliva obtained from BPD patients undergoing Dialectic Behavioral Therapy (DBT) compared to healthy control (HC) participants. Associations with ACE and BPD symptom severity were assessed, and therapy-related changes in DNAm were examined. Results: At baseline, BPD patients demonstrated significant hypomethylation of PRDM8 in blood relative to the HC group. Following DBT, a nominally significant increase in DNAm was observed, aligning with inversely correlated symptom severity. No significant differences in saliva were detected. ACE was not associated with PRDM8 DNAm. Conclusions: Our findings suggest that PRDM8 DNAm might be associated with BPD and therapeutic intervention but not with ACE. Together with prior research, the results underscore the importance of future investigation of gene–environment interactions and the functional significance of PRDM8 regulation in the pathophysiology of BPD. Full article

Background/Objectives: The Germ Cell Theory of cancer posits that human primordial germ cells (hPGCs) are the cells of origin for malignancies. While this theory is well established for germ cell cancers, a germ cell origin for somatic cancers has been largely overlooked despite clinical observations of malignant somatic transformation (MST), wherein germ cell cancers give rise to diverse somatic cancer phenotypes, often without additional mutations. Methods: To test the Germ Cell Theory experimentally in somatic cancer, we established a virus-driven MST model linking hPGC-like cells (hPGCLCs) to Merkel cell polyomavirus (MCPyV)-positive Merkel cell carcinoma (MCC), a highly aggressive somatic cancer with a germ cell cancer-like, low-mutation epigenetic profile. The MCPyV genome was transduced into human induced pluripotent stem cells (hiPSCs) or hPGC-like cells by lentiviral transfection, followed by xenotransplantation. Results: Virus-positive MCC (VP-MCC)-like tumors were consistently induced without additional oncogenic mutations. These tumors recapitulated VP-MCC’s high-grade neuroendocrine carcinoma histology and molecular profiles. DNA methylation analysis revealed near-complete global hypomethylation in VP-MCC-like tumors, matching the unique epigenetic state of late-stage hPGCs. Notably, pluripotent intermediates were neither necessary nor sufficient for MST; transformation required acquisition of a late-hPGC-like epigenetic state. Conclusions: This is the first MST model of a somatic cancer arising through an aberrant germline-to-soma transition. Our findings unify VP-MCC and germ cell cancer biology, challenge mutation- and soma-centric paradigms, and provide a tractable platform to investigate developmental and epigenetic mechanisms of oncogenesis. This MST model supports a unifying germ cell origin for both germ cell and non-germ cell somatic malignancies. Full article

Epigenetic regulation is critical to B cell development, guiding gene expression via DNA methylation, histone modifications, chromatin remodeling, and noncoding RNAs. In mature B cell neoplasms, particularly diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL), these mechanisms are frequently disrupted. Recurrent mutations in key epigenetic regulators such as EZH2, KMT2D, CREBBP, and TET2 lead to altered chromatin states, repression of tumor suppressor genes, and enhanced oncogenic signaling. Dysregulation of specific microRNAs (e.g., miR-155, miR-21) further contributes to pathogenesis and therapeutic resistance. In DLBCL, hypermethylation of SMAD1 and CREBBP mutations are associated with immune evasion and chemoresistance. In FL, EZH2 gain-of-function and KMT2D loss-of-function mutations alter germinal center B cell programming, while in CLL, DNA hypomethylation patterns reflect the cell of origin and correlate with clinical outcome. Targeted therapies such as the EZH2 inhibitor tazemetostat have demonstrated efficacy in EZH2-mutant FL, while HDAC and BET inhibitors show variable responses across B cell malignancies. The limitations of current epigenetic therapies reflect the complexity of targeting epigenetic dysregulation rather than therapeutic futility. These challenges nonetheless highlight the relevance of epigenetic alterations as biomarkers and therapeutic targets, with potential to improve the management of mature B cell neoplasms. Full article

Background/Objectives: Nutrigenomics explores how dietary components influence genome function, especially via epigenetic mechanisms like DNA methylation. A key challenge is identifying healthy food-derived molecules capable of counteracting epigenetic damage from harmful dietary elements. Pistachio nuts (Pistacia vera L.), particularly the Bronte variety from Sicily, are rich in antioxidant polyphenols. In this study we used a methylomic approach to assess the nutrigenomic potential of a hydrophilic extract from Bronte pistachio (BPHE) in a model of human intestinal epithelium, as well as its capacity to modulate arsenic (As)-induced epigenotoxicity. Methods: BPHE was obtained via ethanol/water Soxhlet extraction. CaCo-2 cells were treated with BPHE, alone and after exposure to sodium arsenite. The methylation pattern of the genomic DNA was assessed by methylation-sensitive arbitrarily primed PCR and the methylomic signature was defined by Next-generation bisulfite sequencing. Results: BPHE alone did not alter DNA methylation pattern but, at the highest dose, modulated the changes induced by As. The identification of differentially methylated gene promoters in cell treatment vs. untreated controls revealed that BPHE and As primarily induced hyper-methylation, with a synergistic effect when combined. In particular, all the treatments increased methylation levels of gene categories such as pseudogenes, key genes of specific pathways, genes for zinc-finger proteins, homeobox proteins, kinases, antisense RNA, and miRNA. Notably, in co-treatment with As, BPHE promoted hypo-methylation of genes involved in tumor suppression, detoxification, mitochondrial function, and cell division. Conclusions: These findings suggest that Bronte pistachio polyphenols may epigenetically steer gene expression toward a protective profile, reducing risks of genomic instability and disease. This supports their potential as nutraceuticals to counter harmful epigenetic effects of toxic food components like arsenic. Full article

Fetal exposure to antiseizure medications (ASMs) can impact organogenesis, resulting in elevated risk of congenital malformations. Despite longstanding clinical awareness of the teratogenic potential of ASMs, the molecular mechanisms remain largely unexplored. To address this multisystem impact of ASMs, an OMIC-based approach was considered to understand the impact of ASMs on methylome and subsequently on proteome and how folic acid (FA) supplementation can counter the teratogenic impact. The study employed an established in vitro embryonic cell line model system, treated with varying concentrations of first-generation ASMs, alone and in combination with FA. Integrated analyses included quantification of global DNA methylation, expression analysis of key epigenetic regulators (DNMTs and TETs), genome-wide methylation profiling using the 935K EPIC array, and LC-MS/MS-based proteomics analysis. The study identified that ASMs can induce global DNA hypomethylation, which was likely to be impacted by dysregulation of DNMT and TET expression. Interestingly, FA co-treatment partially restored DNA methylation as evidenced by global DNA methylation and epigenetic gene expression, and also by compensatory effect via one-carbon metabolism. Genome-wide DNA methylation revealed site-specific hypermethylation at key developmental genes, several of which were reversed with FA. Proteomics analysis identified downregulation of developmentally critical proteins, including those linked to key metabolic processes, while FA co-treatment reversed expression of several such proteins. Integrative methylome–proteome analysis revealed the coordinated regulation of target genes that are linked to congenital abnormalities. Together, these findings offer mechanistic insight into ASM-induced teratogenesis and support FA’s potential to mitigate epigenetic and proteomic disruptions. This integrated OMICs based approach identifies key biomarkers which can be used for therapeutic monitoring and help in optimizing maternal epilepsy management. Full article

Background: Robust evidence supports the role of tetrahydrobiopterin (BH4) metabolism in sustaining inflammation; however, the mechanisms underlying the persistent upregulation of the BH4 pathway remain incompletely understood. This study investigated the epigenetic regulation of BH4 metabolism following a single injection of lipopolysaccharide (LPS) in the mouse hippocampus. Methods: Male C57BL/6J mice received either saline or LPS (0.33 mg/kg, i.p.) and were sacrificed at 4 h or 24 h post injection. Behavioral assessments and analyses of hippocampal neurotransmitter metabolism, DNA methylation profile, oxidative stress, and inflammasome activation were performed. Neopterin levels, a marker of immune system activation, were measured in both the plasma and hippocampus. Results: LPS-treated mice exhibited sickness behavior, including reduced locomotor and exploratory activity at both 4 and 24 h. While exploratory behavior showed partial recovery by 24 h, locomotor activity remained impaired. Neopterin levels increased in both the plasma and hippocampus following LPS administration but returned to baseline in the hippocampus by 24 h. Despite the normalization of neopterin, a persistent pro-inflammatory state in the hippocampus was evident at 24 h, as shown by increased expression of Ikbkb and components of the NLRP3 inflammasome, along with elevated oxidative stress markers. Upregulation of Nrf-2 and Hmox1 suggested activation of a protective antioxidant response. Dopaminergic metabolism was disrupted, indicating impaired BH4-dependent dopamine turnover. Epigenetic analysis revealed increased expression of DNA methyltransferases (Dnmt1, Dnmt3a, Dnmt3b) and Tet2, along with reduced expression of Tet1 and Tet3. Promoter hypomethylation of Gch1 and Ptps was observed, correlating with increased hippocampal expression and potentially elevated BH4 levels. Conclusions: Together, these findings show that a single LPS challenge was sufficient to induce the activation of the BH4 synthesis pathway during the late acute inflammatory phase, both systemically and in the hippocampus, potentially driven by epigenetic modifications such as promoter hypomethylation. This may contribute to the perpetuation of neuroinflammation. Full article

Background/Objectives: Esophageal and esophagogastric junction adenocarcinoma (EADC-EGJA), which mainly develops from Barrett’s esophagus (BE), low-grade dysplasia (LGD), and high-grade dysplasia (HGD), has a poor prognosis and several unmet clinical needs, among which is the detection of minimal residual disease (MRD) after endoscopic/surgical resection. Long interspersed nuclear element-1 (LINE-1), a surrogate marker of global methylation, is considered an emerging biomarker for MRD monitoring. The aim of this study was to determine, by LINE-1 methylation analysis, at which carcinogenesis step global methylation is affected and whether this biomarker could be followed in longitudinal to monitor the disease behavior post-surgery. Methods: Cell-free DNA of 90 patients with non-dysplastic Barrett’s esophagus (NDBE), HGD/early EADC-EGJA, or locally advanced/advanced EADC-EGJA were analyzed for LINE-1 methylation, by Methylation-Sensitive Restriction Enzyme droplet digital PCR (MSRE-ddPCR). Twenty-six patients were longitudinally studied by repetitive blood sampling. Results: Global hypomethylation increased during carcinogenesis, with significant difference between locally advanced/advanced EADC-EGJA and NDBE patients (p = 0.028). Longitudinal cases confirmed the rareness of hypomethylation in NDBE cases. The majority of HGD/early EADC-EGJA and locally advanced/advanced EADC-EGJA patients showed methylation changes after resection according to clinical status. Conclusions: This study suggests that global hypomethylation occurs just prior to cancer invasiveness and that it is a promising biomarker to monitor MRD. Full article

Basal-like breast cancer (BLBC) is associated with poor prognosis, high recurrence rates, and limited therapeutic options, largely due to its molecular heterogeneity and complexity, which include epigenetic alterations. This study investigated epigenetic regulatory networks in BLBC by analyzing DNA methylation in distal cis-regulatory regions and its impact on genes, transcription factors (TFs), and microRNAs (miRNAs) expression. Data from TCGA were processed using the ELMER and DESeq2 tools to identify differentially methylated regions and differentially expressed genes, TFs, and miRNAs. The FANMOD algorithm was used to identify the regulatory interactions uncovering the feed-forward loops (FFLs). The analysis identified 110 TF-mediated FFLs, 43 miRNA-mediated FFLs, and five composite FFLs, involving 18 hypermethylated and 32 hypomethylated genes, eight upregulated and nine downregulated TFs, and 21 upregulated and seven downregulated miRNAs. The TF-mediated FFLs major regulators involved the AR, EBF1, FOS, FOXM1, and TEAD4 TFs, while key miRNAs were miR-3662, miR-429, and miR-4434. Enriched pathways involved cAMP, ErbB, FoxO, p53, TGF-beta, Rap1, and Ras signaling. Differences in hallmark gene set categories reflected distinct methylation and miRNA expression profiles. Overall, this integrative analysis mapped the intricate epigenetic landscape of BLBC, emphasizing the role of FFLs as regulatory motifs that integrate DNA methylation, TFs, and miRNAs in orchestrating disease’s development and progression and offering potential targets for future diagnostic and therapeutic strategies. Full article

Uterine leiomyomas (ULM) and uterine leiomyosarcomas (ULMS) represent smooth muscle tumors with similar initial presentations but drastically different outcomes. This literature review analyzes the similarities and differences in their epigenetic profiles to identify diagnostic biomarkers and potential therapeutic targets that could improve clinical management. Both tumor types exhibit mostly distinct epigenetic signatures while sharing key pathway dysregulations. ULMS demonstrates global DNA hypomethylation, increased histone acetyltransferase activity, elevated Histone Deacetylase (HDAC) class I expression, and characteristic microRNA profiles. ULM displays focal methylation patterns and specific microRNA alterations that promote extracellular matrix accumulation. Despite these differences in epigenetic mechanisms, both tumors converge on dysregulation of signaling pathways including PI3K/AKT/mTOR, Wnt/β-catenin, and Transforming Growth Factor beta (TGF-β) signaling, suggesting common downstream effects from distinct epigenetic origins. Understanding the shared and distinct epigenetic landscape between ULM and ULMS will enhance our insights into tumor pathogenesis and may offer promising biomarkers and therapeutic targets. Full article

Age-related macular degeneration (AMD) is one of the leading causes of irreversible vision loss among the elderly, and is influenced by a combination of genetic and environmental risk factors. While genetic associations in AMD are well-established, the molecular mechanisms underlying disease onset and progression remain poorly understood. A growing body of evidence suggests that epigenetic modifications may serve as a potential missing link regulating gene–environment interactions. This review incorporates recent findings on DNA methylation, including both hypermethylation and hypomethylation patterns affecting genes such as silent mating type information regulation 2 homolog 1 (SIRT1), glutathione S-transferase isoform (GSTM), and SKI proto-oncogene (SKI), which may influence key pathophysiological drivers of AMD. We also examine histone modification patterns, chromatin accessibility, the status of long non-coding RNAs (lncRNAs) in AMD pathogenesis and in regulating pathways pertinent to the pathophysiology of the disease. While the field of ocular epigenetics remains in its infancy, accumulating evidence to date points to a burgeoning role for epigenetic regulation in AMD, pre-clinical studies have yielded promising findings for the prospect of epigenetics as a future therapeutic avenue. Full article

Bone metastasis remains a significant cause of morbidity and diminished quality of life in patients with advanced breast, prostate, and lung cancers. Emerging research highlights the pivotal role of reversible epigenetic alterations, including DNA methylation, histone modifications, chromatin remodeling complex dysregulation, and non-coding RNA networks, in orchestrating each phase of skeletal colonization. Site-specific promoter hypermethylation of tumor suppressor genes such as HIN-1 and RASSF1A, alongside global DNA hypomethylation that activates metastasis-associated genes, contributes to cancer cell plasticity and facilitates epithelial-to-mesenchymal transition (EMT). Key histone modifiers, including KLF5, EZH2, and the demethylases KDM4/6, regulate osteoclastogenic signaling pathways and the transition between metastatic dormancy and reactivation. Simultaneously, SWI/SNF chromatin remodelers such as BRG1 and BRM reconfigure enhancer–promoter interactions that promote bone tropism. Non-coding RNAs, including miRNAs, lncRNAs, and circRNAs (e.g., miR-34a, NORAD, circIKBKB), circulate via exosomes to modulate the RANKL/OPG axis, thereby conditioning the bone microenvironment and fostering the formation of a pre-metastatic niche. These mechanistic insights have accelerated the development of epigenetic therapies. DNA methyltransferase inhibitors (e.g., decitabine, guadecitabine) have shown promise in attenuating osteoclast differentiation, while histone deacetylase inhibitors display context-dependent effects on tumor progression and bone remodeling. Inhibitors targeting EZH2, BET proteins, and KDM1A are now advancing through early-phase clinical trials, often in combination with bisphosphonates or immune checkpoint inhibitors. Moreover, novel approaches such as CRISPR/dCas9-based epigenome editing and RNA-targeted therapies offer locus-specific reprogramming potential. Together, these advances position epigenetic modulation as a promising axis in precision oncology aimed at interrupting the pathological crosstalk between tumor cells and the bone microenvironment. This review synthesizes current mechanistic understanding, evaluates the therapeutic landscape, and outlines the translational challenges ahead in leveraging epigenetic science to prevent and treat bone metastases. Full article

Aberrant DNA methylation has been shown to be a fingerprint characteristic in human colorectal tumors. In this study, we hypothesize that investigating global DNA methylation could offer potential candidates for clinical application in CRC. The epigenome-wide association analysis was conducted in both the tumor area (N = 27) and the adjacent tumor-free (NAT) area (N = 15). We found 78,935 differentially methylated CpG sites (DMCs) (FDR < 0.05), 42,888 hypomethylated and 36,047 hypermethylation showing overall hypomethylation. Gene ontology and KEGG analysis of differentially methylated genes showed significant enrichment in developmental genes, as well as in genes involved in metabolic processes and the cell cycle, such as the TFGβ and cAMP signaling pathways. Through filtered analysis, we identified TNXB as the most epigenetically dysregulated gene, hypomethylated and downregulated in CRC (both with p < 0.001) and associated with poor overall survival. In the functional analysis, TNXB was epigenetically regulated in a dose-dependent manner, suggesting a potential role in CRC. The epigenetic dysregulation and functional role of TNXB in CRC could have clinical implications, serving as indicators of malignant potential, with adverse effects associated with disease origin and progression in CRC. Full article

Abiotic stress can reprogram the gametophytic pathway; the mechanisms by which floral bud pre-treatment influences microspore embryogenesis initiation remain unclear. In this study, we use bisulfite sequencing, sRNA-seq, and RNA-seq to analyze the dynamic changes in rice microspores under different cold treatment durations. Our results showed that a 10-day cold treatment is essential for CXJ microspore embryogenesis initiation. DNA methylation levels showed a slight change at CG, CHG, and CHH sites under cold treatment. The number of both hyper- and hypomethylated DMRs increased over cold treatment, with more hypermethylated DMRs at 5 and 10 dpt. Hypermethylated DMRs were more frequently in the TSS region compared to hypomethylated DMRs. The proportion of 24 nt sRNAs increased upon cold stress, with more downregulated than upregulated sRNAs at 10 dpt. The number of DMR target DEGs increased from 5 to 10 dpt. Promoter hypomethylation at the CHH site was more frequently associated with DEGs. These outcomes suggested that the RdDM pathway participates in the initiation of rice ME. GO analysis indicated that DMR target DEGs at 10 dpt were enriched in responses to chemical stimuli, biological processes, and stress responses. An auxin-related gene, OsHOX28, was further identified. Its upregulation, potentially mediated by the RdDM pathway, may play a crucial role in the initiation of rice ME. This study provides more information on epigenetic mechanisms during rice ME. Full article