Epigenetics最新文献

DNA methylation is a well-studied epigenetic factor and has become a powerful player in the cancer biomarker research field. Together with the rising interest in methylation biomarkers, the technological advances for the detection of DNA methylation have been immense. This has led to a plethora of different methods. The first methods were established for DNA methylation detection in genomic DNA, while new methods have focused more on compatibility with the emerging interest of cell-free DNA (cfDNA) from liquid biopsies. As DNA methylation detection in cfDNA brings its own challenges, a shift from the gold standard bisulfite conversion towards enzymatic conversion methods can be observed in recent years. In this review, we aim to summarize the classic and more recent DNA methylation detection methods for liquid biopsies. Importantly, the few existing European Certified In Vitro Diagnostics (CE-IVD) clinical applications for liquid biopsies are also described, underlining the potential of DNA methylation as a detection biomarker in cfDNA. Furthermore, we provide some insights into how the field might evolve in the future, where we believe enzymatic conversion might become a new gold standard and direct sequencing methods, such as ONT-sequencing, will get an important place in the epigenetic research field. Lastly, we believe that multi-omics technologies, which can combine diverse types of biomarkers, will most likely become more important in future clinical applications. Moreover, novel recent technologies are being developed and show promising clinical applications. Taken together, methylation biomarkers are becoming more important for clinical implementation.

WD40-repeat-containing protein 5 (WDR5) is a highly conserved multifunctional scaffold protein with a toroidal structure, facilitating interactions with numerous partners through its WDR5-binding motif (WBM) and WDR5-interacting (WIN) sites. It plays a critical role in histone modifications, including H3K4 methylation (H3K4me), histone acetylation, and deacetylation, influencing stem cell maintenance and differentiation. Recent studies highlight its involvement in muscle homeostasis, particularly in skeletal muscle progenitor cells, where it regulates PAX7-driven myogenic factor expression. Additionally, WDR5 governs epigenetic programs in smooth muscle by modulating H3K4me marks on lineage-specific genes. Despite extensive research on its role in cancer and chromatin remodeling, its broader physiological functions remain underexplored. This review examines WDR5's regulatory mechanisms, including its modulation by long non-coding RNAs (lncRNAs), post-translational modifications (PTMs), and microproteins, while emphasizing its relevance to muscle biology. Understanding WDR5's interactome and regulatory networks could provide novel insights into muscle regeneration, stem cell dynamics, and potential therapeutic strategies for muscular disorders and regenerative medicine.

Glaucoma is a major cause of blindness globally and its prevalence rises with age. This study explored systemic blood-derived DNA methylation epigenetic biomarkers for association with glaucoma and intraocular pressure (IOP). Blood-derived DNA methylation (DNAm) was analyzed in 1,201 European participants from the Canadian Longitudinal Study on Aging (CLSA; Illumina EPIC v1 array) and 843 European participants from TwinsUK (450k array). An Epigenome-Wide Association Study (EWAS) for glaucoma and IOP was conducted, adjusting for age, sex, tobacco smoking, and leukocyte cell types. DNAm-based EpiScores estimates for 108 plasma protein levels were evaluated for associations with glaucoma and IOP. Additionally, 'biological' age acceleration, estimated using five established DNAm 'clocks,' was assessed for glaucoma and IOP and replicated in The Health and Retirement Study (HRS; n = 3,453). EWAS analyses of glaucoma and IOP in individual cohorts did not identify genome-wide significant associations. However, a combined EWAS for overlapping probes in both cohorts identified two epigenome-wide significant CpGs: cg03498697 in the FRMD3 promoter (p = 6.86x10^-8) and cg06044751 intronically within PALLD (p = 1.76x10^-7). EpiScore analysis revealed one IOP Bonferroni-significant association with TNFRSF1B levels in the meta-analysis of both cohorts (p = 1.31x10^-4). DNAm 'clock' analysis in the HRS identified a GrimAge-positive age acceleration associated with glaucoma (p = 0.01). This study identified significant epigenetic blood-derived biomarkers that are associated with glaucoma and IOP. These findings warrant replication in larger and more diverse populations as well as via longitudinal analysis to assess their robustness and potential predictive power.

This review explores how anesthetic agents influence epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNA expression, and their lasting clinical effects. Common anesthetics, including propofol, isoflurane, sevoflurane, and local or regional agents, trigger epigenetic alterations. Preclinical research, especially in developing and aging brains, ties these changes to neurodevelopmental delays, cognitive decline, and shifts in immune and metabolic processes. While clinical studies are ongoing, accumulating evidence reveals that anesthesia triggers both transient and persistent epigenetic modifications, with potential links to postoperative cognitive dysfunction, prolonged inflammation, and altered developmental trajectories. Pediatric and elderly patients show heightened susceptibility due to brain plasticity or diminished resilience. Leveraging epigenetic knowledge could pave the way for tailored anesthesia approaches, reducing long-term risks. Moreover, emerging evidence suggests intergenerational transmission of these epigenetic changes via germline reprogramming, potentially affecting neurodevelopment and disease susceptibility in offspring. Future studies should prioritize large-scale human trials, detailed mechanistic insights, and identification of epigenetic biomarkers to guide safer anesthetic development. This review highlights anesthesia's broader systemic consequences, extending beyond immediate cognitive impacts, and underscores its relevance to personalized medicine.

Menstrual effluent cell profiles have potential as noninvasive biomarkers of female reproductive and gynecological health and disease. We used DNA methylation-based cell type deconvolution (methylation cytometry) to identify cell type profiles in self-collected menstrual effluent. During the second day of their menstrual cycle, healthy participants collected menstrual effluent using a vaginal swab, menstrual cup, and pad. Immune cell proportions were highest in menstrual cup samples, and epithelial cells were highest in swab samples. Our work demonstrates the feasibility and utility of menstrual effluent cell profiling in population-level research using remotely collected samples and DNA methylation.

Insulin resistance (IR) is a risk factor for cardiovascular diseases and type 2 diabetes. Associations between DNA methylation (DNAm) and IR have been less studied in African ancestry (AA) populations than those of European ancestry (EA). We aimed to identify associations between whole blood DNAm and IR in up to 1,811 AA and 964 EA participants from the Atherosclerosis Risk in Communities (ARIC) study. We quantified IR using three surrogate measures: the homeostasis model assessment of insulin resistance (HOMA-IR), the triglyceride-glucose index (TyG), and the triglyceride glucose-body mass index (TyG-BMI). We used ancestry-stratified linear regression models to conduct epigenome-wide association studies of IR, adjusting for batch effects and relevant covariates. Among 484,436 tested CpG sites, 39 were significantly associated with IR, of which 31% (10 in AA and two in EA) were associated with TyG-BMI and not previously reported for IR or related traits. These include a positive association at cg18335991-SEMA7A in AA. SEMA7A inhibits adipogenesis of preadipocytes and lipogenesis of mature adipocytes. DNAm levels at cg18335991 have been reported to be negatively associated with SEMA7A expression in blood. After additionally adjusting for smoking and drinking status, 15 of the 39 significant CpG sites remained significant or suggestive. Our study identified novel IR-associated CpG sites, contributing to a broader understanding of the epigenetic mechanisms underlying IR in diverse populations.

During fertilization, spermatozoa contribute genetic and epigenetic factors such as chromatin packaged with protamines and histones; DNA methylome, non-coding RNAs, etc. Human sperm chromatin retains 5-15% nucleosomes which can play a key role in embryonic development. Recurrent pregnancy loss (RPL) is a condition mainly attributed to defects in embryo and placenta development. Majority of the known RPL factors are of maternal contribution, while  ~50% RPL cases are termed idiopathic (iRPL). In addition to paternal genetic factors, epigenetic factors via sperm could also be responsible for iRPL. Hence, we investigated alterations in retained nucleosome content of iRPL sperm (n = 46) as compared to fertile male population (n = 40). We measured the relative abundance of core histone H4 and Protamine-2 content along with the modified histones H4Ac, H3K4me3, H3K27me3 and H3K9me3 by flow cytometry. H4 and Protamine-2 levels were comparable in both groups and showed significant negative correlation. The iRPL group had significantly higher levels of sperm H3K4me3 as compared to the fertile control group. The other modified histones and protamine levels showed no significant alterations. Furthermore, sperm DFI was found to be significantly positively correlated with H4 levels in both groups. No significant correlation was observed between sperm 5-mC levels with H4 and other modified histone levels. A fraction of H3K4me3 enrichment is now known to resist embryonic epigenetic reprogramming; and hence, such elevated levels in the sperm would question its developmental competence leading to RPL pathology. Also, incidence of sperm DNA fragmentation is associated with increased histone retention in both fertile and iRPL cases.

The glucocorticoid receptor (GR) is a critical nuclear receptor that regulates gene expression in diverse tissues, including the heart, where it plays a key role in maintaining cardiovascular health. GR signaling influences essential processes within cardiomyocytes, including hypertrophy, calcium handling, and metabolic balance, all of which are vital for proper cardiac function. Dysregulation of GR activity has been implicated in various cardiovascular diseases (CVDs), highlighting the potential of GR as a therapeutic target. Remarkably, recent insights into GR's epigenetic regulation and its interaction with circadian rhythms reveal opportunities to optimize therapeutic strategies by aligning glucocorticoid administration with circadian timing. In this review, we provide an overview of the glucocorticoid receptor's role in cardiac physiology, detailing its genomic and non-genomic pathways, interactions with epigenetic and circadian regulatory mechanisms, and implications for cardiovascular disease. By dissecting these molecular interactions, this review outlines the potential of epigenetically informed and circadian-timed interventions that could change the current paradigms of CVD treatments in favor of precise and effective therapies.

Acute urticaria can be a presenting symptom of anaphylaxis characterized by transient red swellings or fulminant wheals, often accompanied by severe pruritus. Numerous studies have substantiated the important involvement of regulatory T cells (Tregs) in the occurrence of allergic diseases and autoimmune diseases. However, the role of Tregs in the pathogenesis of acute urticaria is unclear. In this study, we found that the frequency of Tregs in peripheral blood mononuclear cells (PBMCs) was decreased in patients with acute urticaria compared with normal controls by flow cytometry. Analysis of Assay for transposase-accessible chromatin with sequencing (ATAC-seq) data identified 28 differentially accessible regions comparing Tregs from healthy individuals and patients with acute urticaria, all showing increased chromatin accessibility in the Tregs from acute urticaria. IL-1b was highly expressed in sera of patients with acute urticaria and the level of IL-1b was moderately positively related to white blood cell count. The elevated expression of IL-1b may be due to the diminished immune-suppressive function following the decline of Tregs in this study. We found that IL1B gene expression was also significantly increased in the skin lesions of both chronic spontaneous urticaria and solar urticaria compared to healthy controls. IL1B might play a key role in the development of acute urticaria and IL1B could be a potential prognostic biomarker and therapeutic target in urticaria.

Paternal influence on the offspring epigenome is difficult to interpret in observational human studies due to heterogeneous designs, causing varying susceptibility to bias and non-causal explanations. We conducted a systematic review (CRD42022302695) of paternal exposures before or during pregnancy in relation to the offspring epigenome, focusing on characteristics affecting causal interpretation and reproducibility. We searched three electronic databases for human studies published between 2003 and 2023. Eligible studies assessed paternal factors before or during pregnancy as exposures, and epigenetic mechanisms as outcomes. Risk of bias (RoB) was evaluated using ROBINS-E. The most frequently studied paternal factors were BMI/obesity (7), age (7), smoking (5), and socioeconomic status (SES) (4). All 28 studies assessed DNA methylation; two additionally explored miRNA expression. Most studies were rated 'high' or 'very high' RoB, primarily due to unclear exposure measurement and confounding. Findings showed limited overlap in CpG sites and genomic regions across studies. However, exposures that were stable (e.g. SES) or had clearly defined timing produced more consistent results. Notably, studies with clearly defined timing of paternal smoking suggested preconception exposure may influence offspring epigenetic pathways related to innate immunity but not pregnancy exposure. In contrast, paternal factors with poorly defined experimental analogues, such as BMI, provided inconsistent results. Aligning study design more closely with clinical trials or animal models, by clearly defining populations and exposures, may result in more reliable and replicable findings. Frameworks like 'target trial emulation,' offer a promising approach to improve reproducibility and interpretability of future research on paternal effects on offspring epigenome.