Search Results (160)

The bidirectional relationship between epilepsy and depression illustrates shared neurobiological mechanisms of neuroinflammation, hypothalamic–pituitary–adrenal axis dysregulation, and glutamatergic dysfunction. Depression is present in 20–55% of people with epilepsy, far greater than in the general population, while depression doubles epilepsy risk 2.5-fold, indicating shared pathophysiology. Neuroinflammatory mediators (interleukin-6, tumor necrosis factor alpha, high-mobility group box 1) establish a vicious cycle: seizures exacerbate inflammation and mood disruption, and stress lowers seizure thresholds. Hippocampal damage and cortisol toxicity also link these disorders, with early life stress imprinting lifelong risk via epigenetic alteration. Genetic studies identify pleiotropic genes (brain-derived neurotrophic factor) that regulate synaptic plasticity, serotonin activity, and immune responses. New treatments target shared pathways: ketamine and AMPAkines normalize glutamate tone; mGluR5 antagonists attenuate hyperexcitability and inflammation; DNA methyltransferase inhibitors reverse aberrant DNA methylation; and probiotics manipulate the gut–brain axis by boosting neuroprotective metabolites like butyrate. Despite challenges—transient effects, precision dosing, and blood–brain barrier penetration—these advances constitute a paradigm shift toward mechanistic repair rather than symptom management. The way forward includes clustered regularly interspaced short palindromic repeats (CRISPR)-based epigenome editing, biomarker-led therapies, and combination approaches (e.g., ketamine and probiotics). Such comorbidity needs to be managed holistically through integrated neuropsychiatry care, offering hope to patients with treatment-refractory symptoms. Full article

Numerous infants have been conceived by in vitro fertilization (IVF) and other assisted reproductive technologies (ART). Increasing evidence indicates that these approaches induce minor alterations in molecules during the initial phases of embryogenesis. This narrative review examines the molecular pathophysiology of embryonic cardiogenesis in the context of assisted reproductive technology, emphasizing transcriptional and epigenetic regulation. Essential transcription factors for cardiac development, including NKX2-5, GATA4, TBX5, ISL1, MEF2C, and HAND1/2, play a crucial role in mesodermal specification, heart tube formation, and chamber morphogenesis. Animal models and human preimplantation embryos have demonstrated that ART-related procedures, including gamete micromanipulation, supraphysiological hormone exposure, and extended in vitro culture, can alter the expression or epigenetic programming of these genes. Subsequent to ART, researchers have identified anomalous patterns of DNA methylation, alterations in histones, and modifications in chromatin accessibility in cardiogenic loci. These alterations indicate that errors occurred during the initial reprogramming process, potentially resulting in structural congenital heart abnormalities (CHDs) or modifications in cardiac function later in life. Analysis of the placental epigenome in babies conceived using assisted reproductive technology reveals that imprinted and developmental genes critical for cardiac development remain dysfunctional. This review proposes a mechanistic theory about the potential subtle alterations in the cardiogenic gene network induced by ART, synthesizing findings from molecular embryology, transcriptomics, and epigenomics. Understanding these molecular issues is crucial not only for enhancing ART protocols but also for evaluating the cardiovascular risk of children conceived by ART postnatally and for early intervention. Full article

Benzene, a well-established human carcinogen and major industrial pollutant, poses significant health risks through occupational exposure due to its no-threshold effect, leading to multi-system damage involving the hematopoietic, nervous, and immune systems. This makes the investigation of its toxic mechanisms crucial for precise prevention and control of its health impacts. Programmed cell death (PCD), an orderly and regulated form of cellular demise controlled by specific intracellular genes in response to various stimuli, has emerged as a key pathway where dysfunction may underlie benzene-induced toxicity. This review systematically integrates evidence linking benzene toxicity to PCD dysregulation, revealing that benzene and its metabolites induce abnormal subtypes of PCD (apoptosis, autophagy, ferroptosis) in hematopoietic cells. This occurs through mechanisms including activation of Caspase pathways, regulation of long non-coding RNAs, and epigenetic modifications, with recent research highlighting the IRP1-DHODH-ALOX12 ferroptosis axis and oxidative stress–epigenetic interactions as pivotal. Additionally, this review describes a comprehensive monitoring system for early toxic effects comprising benzene exposure biomarkers (urinary t,t-muconic acid (t,t-MA), S-phenylmercapturic acid (S-PMA)), PCD-related molecules (Caspase-3, let-7e-5p, ACSL1), oxidative stress indicators (8-OHdG), and genetic damage markers (micronuclei, p14ARF methylation), with correlative analyses between PCD mechanisms and benzene toxicity elaborated to underscore their integrative roles in risk assessment. Furthermore, the review details analytical techniques for these biomarkers, including direct benzene detection methods—direct headspace gas chromatography with flame ionization detection (DHGC-FID), liquid chromatography-tandem mass spectrometry (LC-MS/MS), and portable headspace sampling (Portable HS)—alongside molecular imprinting and fluorescence probe technologies, as well as methodologies for toxic effect markers such as live-cell imaging, electrochemical techniques, methylation-specific PCR (MSP), and Western blotting, providing technical frameworks for mechanistic studies and translational applications. By synthesizing current evidence and mechanistic insights, this work offers novel perspectives on benzene toxicity through the PCD lens, identifies potential therapeutic targets associated with PCD dysregulation, and ultimately establishes a theoretical foundation for developing interventional strategies against benzene-induced toxicity while emphasizing the translational value of mechanistic research in occupational and environmental health. Full article

The term chromosomal imprinting was introduced to denote the parent-of-origin-dependent behavior of chromosomes in the fungus gnat originally named Sciara coprophila (current taxonomic name is Bradysia coprophila). Such behavior is observed in Sciara coprophila embryos, where paternal X chromosomes (X_p) are specifically eliminated during the 7th–8th cleavage divisions. Elimination is regulated by a controlling element (CE) that has been mapped to heterochromomere II (H2) within the sub-telomeric short arm of polytene X chromosomes. Here, using a combination of a new Sciara genome assembly, along with ChIP-Seq and MeDIP analyses, we show that a 1.2 Mb region within the CE locus has a repressive epigenetic signature that is characterised by enrichments of H3K9me3, H4K20me3 and 5′-methyl cytosine (5meC). These data provide evidence for a model where the H3K9me3/HP1/H4K20me3 pathway operates to assemble a heterochromatin-like complex at the CE that renders it silent on X_p chromosomes that are not eliminated. In this regard, our findings support the idea that the H3K9me3/HP1/H4K20me3 pathway represents the most evolutionarily conserved mechanism linked to chromosomal imprinting in animals. Full article

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare, often fatal congenital disorder characterized by severe neonatal respiratory distress and associated with complex multisystem malformations. In approximately 90% of cases, the condition is linked to deletions or mutations affecting the FOXF1 gene or its upstream enhancer region on chromosome 16q24.1. This review analyzes reported prenatal cases with 16q24.1 deletion involving FOXF1, aiming to identify recurrent sonographic features and elucidate the underlying genomic and epigenetic mechanisms. We reviewed prenatal cases reported in the literature involving deletions of the 16q24.1 region, including the FOXF1 gene. Here, we expand the case series by reporting a fetus with increased nuchal translucency measuring 8 mm and a de novo 16q24.1 deletion. We identified nine prenatal cases with a 16q24.1 deletion, all involving the FOXF1 gene or its enhancer region. The main ultrasound findings included increased nuchal translucency and cystic hygroma during the first trimester, and cardiac, renal, and intestinal malformations from 20 weeks of gestation onward. Prenatal diagnosis of ACDMPV based solely on ultrasound findings is challenging. In most reported cases, the pregnancy was carried to term, with the diagnosis being confirmed by post-mortem histopathological examination. In the only case in which the pregnancy was terminated at 14 weeks’ gestation, histological examination of the fetal lungs, despite them being in the early stages of development, revealed misaligned pulmonary veins in close proximity to the pulmonary arteries and bronchioles. Evidence highlights the significance of non-coding regulatory regions in the regulation of FOXF1 expression. Differential methylation patterns, and possible contributions of parental imprinting, highlight the complexity of FOXF1 regulation. Early detection through array comparative genomic hybridization (array CGH) or next-generation sequencing to identify point mutations in the FOXF1 gene, combined with increased awareness of ultrasound markers suggestive of the condition, could improve the accuracy of prenatal diagnosis and genetic counseling. Further research into the epigenetic regulation of FOXF1 is crucial for refining recurrence risk estimates and improving genetic counseling practices. Full article

Background/Objectives: The 3-dimensional (3D) architecture of the genome in the nucleus of a living cell plays an unexpected yet fundamental regulatory role in cell biology. As an imprint of the cellular genetic, epigenetic and metabolic status, it discriminates pathological conditions through conditional changes to long-range 3D interactions (up to 300 kb) and thus could act as a powerful molecular biomarker linked closely to clinical outcomes. Methods: Here an assessment is made of the latest paradigm shift in molecular biology from a supply chain where information flows from DNA to RNA to protein, to the concept of heritable 3D folding of the genome reflecting the epigenetic and metabolic state of the cell, and which serves as a molecular biomarker for complex clinical outcome. Results: While biomarkers based on individual components of the supply chain fail to accurately reflect clinical outcomes, 3D genomics offers highly informative insights, exemplified for immuno-oncology and prostate cancer diagnosis by clinical tests of superior performance, already in practice in the US and UK. Conclusions: A more complete understanding of human biology will require models that account for the flow of information to and from the 3D genomic architecture in living cells, together with its regulation and logic. Integrating these principles into biomarker discovery and therapeutic design, along with other frontline approaches in precision medicine, including multi-omics and other system-level tools, will be essential for advancing precision medicine beyond its current limitations. Full article

Genomic imprinting is critical for mammalian development, but its regulation varies across species. The insulin-like growth factor 2 receptor (IGF2R), which is a maternally expressed imprinted gene critical for cell proliferation and differentiation, as well as embryonic and placental development, is classically regulated by differentially methylated regions (DMRs) and lncRNA-Airn in mice. However, studies on this in equus are scarce, especially in terms of mechanistic studies. In the present study, heart, liver, spleen, lung, kidney, brain, and muscle samples were obtained from horses, donkeys, and hybrids, and gene expression and imprinting state were tested to investigate the imprinting regulation of Igf2r in these animals. Bisulfite sequencing combined with an allele-specific expression analysis revealed a tissue-specific loss of imprinting in the mule liver and hybrid brain tissues. Strikingly, we found that the maternal-specific expression of equine Igf2r did not rely on the canonical DMRs or lncRNA-Airn. Surprisingly, DNA methylation of a specific region called CpG island 2 (CpGI2) in the Igf2r promoter showed cis-acting inheritance, meaning that the DNA methylation patterns of the parental alleles are retained in hybrid tissues. Notably, the DNA methylation of CpGI2 correlated negatively with Igf2r expression in the spleen (R² = 0.8797, p = 6.46 × 10⁻⁶), lung (R² = 0.8569, p = 1.57 × 10⁻⁵), and kidney (R² = 0.8650, p = 3.85 × 10⁻⁶). Our findings suggest that imprinting may work differently in other species. This study provides a framework for understanding imprinting diversity in hybrids and shows that equine hybrids can be used to study how epigenetic inheritance works. 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

Background: Uniparental disomy (UPD) is the inheritance of both copies of a chromosome from a single parent, leading to distinct genetic conditions. Maternal UPD of chromosome 6 (UPD(6)mat) is extremely rare, with few molecularly confirmed cases reported. Methods: We report a prematurely born female with isodisomic UPD(6)mat, presenting with intrauterine growth restriction (IUGR), developmental delay, autism spectrum disorder, dysmorphic features, and a sacrococcygeal teratoma. In addition, we reviewed 24 confirmed UPD(6)mat cases to assess clinical patterns in prenatal findings, birth outcomes, and postnatal features. Results: Trio whole-exome sequencing revealed complete isodisomy of chromosome 6 and a de novo heterozygous DIAPH2 variant of uncertain significance. In the literature review, IUGR was present in 87% of cases, with most individuals born small for gestational age and preterm. Failure to thrive and neurodevelopmental issues were also frequent. While the exact molecular basis remains unknown, imprinting disturbances—similar to those in UPD(6)pat—and cryptic trisomy 6 mosaicism, particularly in heterodisomy, are the most likely mechanisms. No specific gene or consistent epigenetic abnormality has been identified. Conclusions: This study aims to enhance the understanding of the genetic and phenotypic spectrum of UPD(6)mat, improving diagnostic and management approaches for this ultra-rare genetic disorder. We propose a detailed list of clinical assessments and tests to be performed following the detection of maternal uniparental disomy of chromosome 6. Full article

Background: Preeclampsia (PE) is a critical complication of pregnancy that affects 3% to 5% of all pregnancies and has been linked to aberrant placentation, causing severe maternal and fetal illness and death. Objectives: This systematic review aims to elucidate the association of in-utero endocrine-disrupting chemical (EDC) exposure and microRNAs and their imprinted genes from prenatal and maternal circulation of PE patients. Methods: Databases such as PubMed, PubMed Central, ScienceDirect, the Comparative Toxicogenomics Database (CTD), ProQuest, EBSCOhost, and Google Scholar were utilized to search for articles that investigate the relationships between selected EDCs and epigenetic events such as DNA methylation and microRNAs that are associated with PE. Results: A total of 29 studies were included in the database search. Altered expression of microRNAs (miR-15a-5p, miR-142-3p, and miR-185) in the placenta of PE patients was positively associated with the urinary concentration of phthalates and phenols in the development of the disease in the first trimester. EDCs such as phenols, phthalates, perfluoroalkyl substances (PFOAs), polybrominated diphenyl ethers (PBDEs), and organochlorine phosphates (OCPs) have been reported to be associated with hypertensive disorders in pregnancy. miRNA-31, miRNA-144, miRNA-145, miRNA-210, placental specific clusters (C14MC, and C19MC) may be used as possible targets for PE because of their potential roles in the onset and progression of PE. Conclusions: Prenatal EDC exposure, including exposure to BPA, showed association with signaling pathways including estrogen, sFlt-1/PlGF, ErbB, MAPK/ERK, and cholesterol mechanisms with placental hemodynamics. Even low EDC exposures leave altered epigenetic marks throughout gestation, which might cause PE complications. Full article

The introduction of extra copies of mitochondrial DNA (mtDNA), whether autologous or heterologous, into oocytes at the time of fertilisation or through other assisted reproductive technologies, such as nuclear transfer, is a contentious issue. The primary focus has been on whether third-party mtDNA is transmitted to the offspring and if it impacts offspring health and well-being. However, little attention has focused on whether the introduction of extra copies of mtDNA will interfere with the balance established between the nuclear and mitochondrial genomes during oogenesis and as the developing embryo establishes its own epigenetic imprint that will influence mature offspring. Whilst we determined that sexually mature offspring generated through mtDNA supplementation did not inherit any-third party mtDNA, they exhibited differences in gene expression from three tissues derived from three separate embryonic lineages. This resulted in a number of pathways being affected. In each case, the differences were greater in the heterologous and autologous comparison than when comparing all supplemented offspring against non-supplemented offspring. Many of the changes in gene expression were coupled to differential DNA methylation across tissues, some of which were tissue-specific, with high levels observed in the heterologous against autologous comparison. An analysis of DNA methylation in blastocyst-stage embryos pointed to changes in patterns of DNA methylation that were transmitted through to the offspring. Our results indicated that extra copies of mtDNA may not be transmitted if introduced at low levels, but the changes induced by supplementation that occur in DNA methylation and gene expression in the blastocyst have a profound effect on tissues. Full article

Background: Prader–Willi syndrome (PWS) is a rare genetic disorder mapping to the imprinted 15q11-13 locus, specifically at the paternally expressed snord116 region, which has been implicated in controlling epigenetic mechanisms. Some aspects of the PWS-related clinical phenotype, such as the high mortality rate in adulthood, might be attributed to accelerated epigenetic ageing. Objectives: The aim of the present case–control study was to evaluate epigenetic age, age acceleration, vascular age (VA), and vascular ageing in adults with PWS (n = 24; F/M = 11/13; age = 36.8 [26.6; 45.3] years; body mass index, BMI = 36.8 [33.9; 44.8] kg/m²), compared with a sex- and age-matched group of subjects with essential obesity (EOB) (n = 36; F/M = 19/17; age = 43.4 [30.6; 49.5] years; BMI = 44.8 [41.2; 51.7] kg/m²). Results: In subjects with PWS, there was a younger epigenetic age and a lower age acceleration than in subjects with EOB. No differences were found between VA and vascular ageing in the two groups. Epigenetic age was associated with chronological age and VA within each group. For each group, no relevant associations of epigenetic age or age acceleration with demographic, biochemical, and clinical parameters were found. When considering individuals with PWS, there were no associations of epigenetic age with growth hormone (GH) deficiency, duration of hormone replacement therapy, and plasma levels of insulin-like growth factor 1 (IGF-1). Conclusions: The hypothesis of accelerated epigenetic ageing in PWS should be rejected. Additionally, considering the existence of a SNORD116-dependent epigenetic dysregulation in PWS, the results of the present study might be misleading, since an epigenetics-based approach was used to measure ageing. Full article

Prostate-specific antigen remains a cornerstone biomarker for prostate cancer diagnosis and management. However, the molecular mechanisms regulating its expression, particularly through DNA methylation, are not fully understood. Here, we report a comprehensive analysis of allele-specific CpG and CCWGG methylation in the proximal PSA promoter across aggressive (PC3), indolent (LNCaP), benign (BPH1), and normal (HPrEpiC) prostate cell lines and provide insights into the unique methylation patterns associated with these states. Our findings reveal that PC3 cells, representing an aggressive PCa phenotype, exhibit complete biallelic methylation of the PSA promoter, leading to PSA gene silencing. Conversely, LNCaP cells display a fully unmethylated promoter with biallelic PSA expression. Interestingly, BPH1 cells display a monoallelic CG/CCWGG methylation pattern, yet fail to express PSA, suggesting imprinting defects or RNA decay mechanisms. Notably, acquisition of biallelic PSA promoter methylation status in PC3 was accompanied by upregulation of DNMT1, whereas unmethylated PSA promoter state in LNCaP was associated with downregulation of DNMT1. These findings highlight distinct methylation patterns in the PSA promoter that differentiate between aggressive, indolent, and benign prostate states. Translating this epigenetic insight into clinical diagnostics could enhance the precision of PSA-based diagnostics, addressing limitations such as false negatives in PSA testing for aggressive PCa. Further exploration of CCWGG methylation’s role in imprinting and monoallelic expression is warranted, particularly in patient-derived samples. Full article

Background and Objectives: Silver–Russell Syndrome (SRS) is a rare genetic disorder characterized by prenatal and postnatal growth restriction, distinctive facial features, and body asymmetry. Early suspicion during the first trimester remains challenging but crucial for optimizing clinical outcomes. This study aims to highlight a diagnostic approach to the early suspicion of SRS. Materials and Methods: A 28-year-old primigravida presented for routine first-trimester prenatal care. An ultrasound revealed asymmetric growth restriction with normal anatomical findings. The first-trimester biochemical markers, including PAPP-A and β-hCG, were within the normal range. A further evaluation, including amniocentesis and genetic testing, was performed. Results: Genetic testing identified hypomethylation at the 11p15 imprinting control region, confirming the diagnosis of SRS. Parental testing excluded the maternal uniparental disomy of chromosome 7, suggesting an epigenetic mechanism. The findings were consistent with a clinical diagnosis of SRS, and appropriate counseling and multidisciplinary management were initiated. Conclusions: This case underscores the importance of the early recognition of atypical growth patterns, the integration of advanced genetic testing, and multidisciplinary counseling to guide parental decision-making and improve outcomes. Full article

DNA methylation (DNAm) regulates gene expression and genomic imprinting. This study aimed to investigate the effect of gastrointestinal (GI) nematode infection on host DNAm. Helminth-free Holstein steers were either infected with Ostertagia ostertagi (the brown stomach worm) or given tap water only as a control. Animals were euthanized 30 days post-infection, and tissues were collected at necropsy. We conducted epigenome-wide profiling using a mammalian methylation array to explore the impact of infection on methylation patterns in the mucosa from abomasal fundus (FUN), pylorus (PYL), draining lymph nodes (dLNs), and the duodenum (DUO). The analysis covered 31,107 cattle CpGs of 5082 genes and revealed infection-driven, tissue-specific, differential methylation patterns. A total of 389 shared and 2770 tissue-specific, differentially methylated positions (DMPs) were identified in dLN and FUN, particularly in genes associated with immune responses. The shared DMPs were found in 263 genes, many of which are involved in immune responses. Furthermore, 282, 244, 52, and 24 differentially methylated regions (DMRs) were observed in dLN, FUN, PYL, and DUO, respectively. More hypomethylated DMRs were detected in dLN and FUN, while more hypermethylated DMRs were found in PYL and DUO. Genes carrying DMPs and DMRs and enriched pathways relating to immune functions/responses were detected in infected animals, indicating a link between DNA methylation and the infection. The data may implicate a crucial role of DNAm in regulating the nature/strength of host immunity to infection and contribute to a deeper understanding of the epigenetic regulatory landscape in cattle infected by GI nematodes. Full article