Clinical Epigenetics最新文献

Background: Fetal growth restriction (FGR) is associated with perinatal complications and potential neurodevelopmental risks, yet mechanistic understanding of metabolic dysregulation remains incomplete. We investigated amniotic fluid metabolites as potential functional biomarkers of fetal-placental dysfunction and explored the possibility of folic acid-mediated epigenetic remediation of metabolic imbalances in FGR.

Results: In FGR amniotic fluid, hypoxanthine was significantly upregulated, valproic acid (VPA) was significantly downregulated, and arginine/proline metabolism pathways were markedly enriched. Folic acid intervention significantly improved fetal growth parameters (crown-rump length, body weight, and placental weight; all P < 0.001). Compensatory labyrinth zone (Lb) hyperplasia was observed in FGR placenta, with a 40% increase in Lb/Jz ratio, while folic acid supplementation reduced Lb proportion by 10% and appeared to restore placental architecture. Epigenetically, folic acid supplementation suppressed histone deacetylases1 (HDAC1) expression, elevated H3K9ac levels and enhanced trophoblast proliferation.

Conclusions: Our research suggests that dysregulation of the VPA-hypoxanthine axis may serve as a hallmark of FGR-associated metabolic stress. Folic acid may exerts potential dual therapeutic effects by correcting placental architecture through Lb normalization and initiating epigenetic reprogramming via HDAC1 inhibition and acetylation at lysine 9 of histone H3 (H3K9ac). These findings indicate that folate metabolism could play a regulatory role in placental gene transcription and fetal growth trajectories.

Context: Silver-Russell syndrome (SRS) is a complex multisystem condition requiring timely diagnosis for appropriate management. A clinical diagnosis is made in individuals scoring ≥ 4 Netchine-Harbison Clinical Scoring System (NH-CSS) criteria, with (epi)genetic investigations undertaken in those with NH-CSS ≥ 3 and strong clinical suspicion. Monogenic variants in imprinted (CDKN1C and IGF2) and non-imprinted (HMGA2 and PLAG1) genes are recognised as rare causes of SRS. The frequency of associated phenotypes is unclear.

Objective: We evaluated the suitability of SRS as an umbrella term for these (epi)genotypes by identifying key clinical features and assessing the validity of NH-CSS.

Methods: An extensive literature search identified 22 IGF2, 18 HMGA2, 11 CDKN1C and 11 PLAG1 published reports.

Main outcome measure: Clinical phenotypes including the NH-CSS criteria were interrogated to assess (dis)similarity between the molecular subgroups of SRS.

Results: Strict adherence to the NH-CSS identified clinical SRS in 91% IGF2, 82% CDKN1C, 78% HMGA2 and 45% PLAG1 affected individuals. Relative macrocephaly was observed in 82% IGF2, 82% CDKN1C, 44% HMGA2, and 27% PLAG1 affected individuals. Prominent forehead was reported in 100% CDKN1C, 91% IGF2, 72% HMGA2, and 64% PLAG1 and body asymmetry in 23% IGF2 and 11% HMGA2 affected individuals. Clinical features not typically associated with SRS included: microcephaly, challenging behaviour, cardiac abnormalities, cleft palate, and asthma.

Conclusions: The NH-CSS missed 9-55% of monogenic SRS. The diverse phenotypes of PLAG1, CDKN1C, HMGA2 and IGF2 variants may hinder a clinical diagnosis of SRS. These rarer (epi)genotypes could be considered as distinct entities.

Trichostatin A (TSA) is a strong epigenetic tool that promises to have the future in the field of immune reprogramming, but its mechanisms of action in patient-derived immune cells in colorectal cancer (CRC) are still poorly studied. We examined in this current study the molecular and functional immune phenotype of lymphocytes of CRC patients and healthy donors in response to low-dose (0.1 nM), short-term (12 h) treatment with TSA, which aims at narrowing cytotoxicity and retaining epigenetic regulation. The TSA potentiated pro-inflammatory cytokines (IFN-gamma, IL-12, TNF-alpha) and inhibited immunoregulatory interleukins (IL-4, IL-10, IL-17, CCL5, Granzyme B in CRC-derived immune cells). At the transcriptional level, TSA induced TBX21 and TP53 and repressed GATA3, FOXP3, RORC, and MYC. Epigenetic profiling showed H3K14ac and H3K4me3 markups, H3K27me3 and HDAC1 downregulation, promoter hypermethylation of immune territory, less R-loop formation, and higher methylation of m6A RNA-partaking in the recommendation that TSA promotes chromatin and transcriptome multilayered modification. The TSA pretreated lymphocytes elicited cytotoxic effect in HT-29 CRC cells and also showed redox disproportion via depletion of glutathione and increase in nitric oxide. Although previous research focuses on the direct impact of TSA on tumor cells, in our study, we exclusively highlight TSA ability to reprogram the immune cells epigenetically in a more inflammatory tumor-reactive phenotype. The findings justify the possibility of TSA as an epigenetic adjunct of low toxicity in immuno-oncology and form a basis to continue in vivo and translational study in CRC immunotherapy.

Glaucoma represents a predominant cause of irreversible blindness globally, characterized by the association of elevated intraocular pressure (IOP) and retinal ganglion cell loss with dysfunction of the trabecular meshwork (TM), the principal tissue regulating conventional aqueous humor outflow. Emerging evidence suggests that this dysfunction is not exclusively driven by genetic variation or mechanical stress; rather, it is significantly influenced by epigenetic mechanisms that integrate factors such as aging, hypoxia/oxidative stress, glucocorticoid exposure, and other environmental challenges into enduring alterations in TM phenotype. This review synthesizes current understanding of the primary epigenetic mechanisms involved in glaucomatous TM remodeling, encompassing DNA methylation, histone modifications, non-coding RNAs (including microRNAs and long non-coding RNAs), and RNA N⁶-methyladenosine (m⁶A) methylation. In this study, we elucidate the role of aberrant DNA methylation in the regulation of profibrotic genes, such as TGF-β1 and GDF7, elasticity-modifying genes like LOXL1, and repetitive elements, which collectively contribute to extracellular matrix (ECM) accumulation, tissue stiffening, and increased outflow resistance. Furthermore, we explore how dysregulated miRNA-lncRNA networks and histone acetylation/methylation influence central signaling pathways, including TGF-β/BMP-Smad, Wnt/β-catenin, RhoA/ROCK, PI3K-Akt, and NF-κB. These pathways are crucial in orchestrating trabecular meshwork (TM) fibrosis, cytoskeletal remodeling, cellular senescence, and impaired stress responses. Additionally, we investigate the emerging roles of m⁶A regulators, such as METTL3, YTHDF2, and YTHDC2, at the intersection of outflow pathway fibrosis and retinal ganglion cell vulnerability. We propose that epigenetic modifiers, ncRNA-based therapies, and partial epigenetic reprogramming could offer innovative, TM-targeted, and neuroprotective strategies beyond conventional IOP-lowering treatments. Collectively, our findings support an integrated model wherein diverse epigenetic modifications converge to produce a stereotypical glaucomatous TM phenotype, thereby presenting novel opportunities for mechanism-based diagnosis and therapeutic intervention in glaucoma.

Background: Cardiovascular diseases (CVD) are influenced by a number of factors, including environmental and genetic components. By linking prospective cohort studies with epigenetics and CVD outcomes, it may be possible to gain insight into the complex mechanisms underlying CVD. This study aims to evaluate the impact of air pollution on CVD and investigate whether DNA methylation (DNAm) mediates the association between air pollution and CVD.

Methods: In the prospective cohort study, the relationship between air pollutants and CVD incidence was analyzed using Cox regression. Dose-response was assessed by the restricted cubic spline model, and multiple pollutants' impact was evaluated by the weighted quantile sum model. The link between genetically predicted DNAm sites related to air pollutants and CVD risk was explored through epigenetic Mendelian randomization (MR), with further evidence provided by gene colocalization analysis.

Results: For every 10 μg/m³ increase, particulate matter with diameters less than 2.5 μm (PM_2.5), particulate matter with diameter less than 10 μm (PM₁₀), nitrogen dioxide (NO₂), and sulfur dioxide (SO₂) increased the risk of CVD by 6.2%, 4.4%, 9.3%, and 6.1%, respectively, with all showing a linear association. Of the four air pollutants, PM₁₀ and PM_2.5 were identified as the most significant contributors to the CVD risk, accounting for 61% and 20%, respectively. Genetically predicted methylation at the PM_2.5-related CpG site cg01065697 was linked to a higher risk of myocardial infarction (MI) and coronary heart disease (CHD), the NO₂-related CpG site cg07091220 was associated with increased MI risk, the NO₂-related sites cg15474579, cg16348358, and cg19869422 were linked to a higher risk of heart failure (HF).

Conclusion: Our study confirms a significant association between air pollution, DNAm and CVD risk, and provides new insights into the pathogenic effects of air pollution on CVD.

Cisplatin resistance remains a major challenge in the clinical treatment of bladder cancer (BC), and the epigenetic regulation of this resistance, particularly involving 5-hydroxymethylcytosine (5hmC), has not been fully elucidated. Here, we investigated the role of 5hmC and vitamin C (VC) in modulating cisplatin sensitivity in BC. Clinical analyses of 36 BC patients receiving cisplatin-based neoadjuvant chemotherapy showed that reduced 5hmC levels in pre-chemotherapy tumor tissues were significantly associated with cisplatin resistance (CR-BC) and poor prognosis, with low 5hmC correlating with shorter progression-free survival (PFS). In vitro, we established two cisplatin-resistant cell lines (T24-CR, UMUC-3-CR) that exhibited reduced 5hmC compared to parental cells. Treatment with 100 μM VC significantly restored 5hmC levels in CR-BC cells by activating TET enzymes, inhibited cell proliferation, and enhanced cisplatin sensitivity; these effects were abrogated by the TET inhibitor Bobcat339, confirming VC acts in a TET-dependent manner. Mechanistically, genome-wide 850 K methylation array and RNA-seq analyses revealed that VC upregulated methylation specifically at the promoter of ATF4, a downstream effector of the MAPK pathway, thereby downregulating ATF4 expression. ATF4 knockdown in CR-BC cells increasing cisplatin sensitivity, while Bobcat339 reversed VC-induced ATF4 downregulation. In vivo, VC combined with cisplatin significantly inhibited tumor growth in T24-CR xenografts, and co-treatment with ATF4 knockdown further enhanced this effect, accompanied by elevated 5hmC and reduced Ki67 in tumors. Collectively, our findings identify reduced 5hmC as a hallmark of cisplatin-resistant BC and reveal a novel mechanism by which VC enhances cisplatin sensitivity. VC activates TET enzymes to increase 5mC at the ATF4 promoter, downregulating ATF4 and modulating the MAPK pathway. This highlights VC as a potential epigenetic adjuvant to overcome cisplatin resistance in BC.

Objectives: Chronic intervillositis of unknown etiology (CIUE) is the pathological influx of maternal inflammatory cells into the intervillous space of the placenta without demonstrable cause. CIUE is associated with placental damage and increased risk of pregnancy loss, fetal demise, and growth restriction. The pathogenic mechanism is unclear, and we lack biomarkers for detection, and treatments to prevent recurrence. DNA methylation (DNAme) is a biomarker altered in association with many disease states. We hypothesized that CIUE may be associated with a distinct signature placental DNAme signature.

Methods: DNAme was profiled using the Illumina Infinium MethylationEPIC v2.0 array on fresh-frozen placental tissue. After quality control, data were available for 24 CIUE (14 high grade, 10 low grade) and 27 non-CIUE placental samples, plus six independent decidua samples. CIUE was confirmed and graded by a perinatal pathologist. Contamination was assessed using the 65 array genotyping probes, placental cell composition and epigenetic age were estimated. After processing, DNAme data were available at 855,732 CpGs.

Results: Several lines of evidence indicated maternal DNA in CIUE placentas. Genetic contamination metrics were higher in CIUE than non-CIUE cases. In XY samples, X chromosome copy number increased with CIUE grade, suggesting XX contaminating DNA. Principal components analysis placed CIUE samples closer to decidua along PC1 than non-CIUE samples, cell composition showed elevated Hofbauer cells, monocytes, and neutrophils in CIUE. Epigenetic age was higher in CIUE versus non-CIUE samples. Together, these findings suggested an increased concentration of non-self XX DNA in CIUE cases, likely originating from an adult, macrophage-rich source, suggesting a maternal origin. An epigenome-wide association study found that all significant differentially methylated loci associated with CIUE were attenuated after adjusting for cell composition.

Conclusions: Our results illustrate that placental DNAme patterns in CIUE reflect signatures of maternal infiltration rather than intrinsic DNAme alterations. This study also highlights the value of integrating the diverse molecular data outputs of DNAme arrays to explore the presence of maternal cells in placental tissue.

Orthostatic hypotension is a sharp decrease in blood pressure when an individual transitions from a supine to an upright position. OH affects at least 30% of older adults. It is attributed to the dysfunction of the autonomic innervation and decreased vascular bed capacity. Genomic (n = 2526), methylomic (n = 910), and transcriptomic (n = 391) data from centenarians aged 90 years and older were used to examine molecular and genetic factors for OH. No statistically significant genetic predictors of OH were identified. However, the study revealed numerous epigenetic markers of OH indicative of general aging, such as DNA hypomethylation. The predictive DNA methylation-based model for orthostatic hypotension demonstrated an average accuracy of 79%. The transcriptome analyses highlighted associations between OH and inflammation pathways, as well as other age-related biological processes. Integrated omics and clinical data have identified six key mechanisms associated with orthostatic hypotension: metabolic dysregulation, impaired muscle tone, altered cell proliferation, inflammation, humoral regulation, and neural regulation.

Bladder urothelial carcinoma (BLCA) is a common malignant tumor with high invasiveness and recurrence rates, underscoring the need for early diagnosis and effective monitoring. Current diagnostic methods, such as invasive cystoscopy and low-sensitivity urine cytology, have limitations. Oncogene hypermethylation plays a key role in tumorigenesis and progression. However, DNA methylation in BLCA remain underexplored. Identifying and validating new DNA methylation markers in urine samples is crucial to enhance early detection accuracy. In this study, we identified three novel BLCA DNA methylation biomarkers (HIST1H3J, NKX2-4, and YBX3P1 genes), and compared with six known markers (ONECUT2, OTX1, POU4F2, SOX1, TWIST1, VIM). Real-time quantitative methylation-specific PCR (qMSP) was used to detect the methylation levels of biomarkers in 319 urine samples from patients with suspected BLCA. The individual biomarkers of HIST1H3J, NKX2-4, and YBX3P1 achieved Areas Under the Curve (AUCs) of 0.892, 0.914 and 0.871, with accuracies of 84.80%, 85.38% and 81.29%, respectively. In comparison, the six known markers exhibited AUCs ranging from 0.850 to 0.939 and the accuracies of 81.87%-88.30%. These methylation markers can not only identify high-grade BLCA but also low-grade BLCA, highlighting their potential clinical utility. Notably, a four-gene panel (ONECUT2, SOX1, TWIST1 and NKX2-4) significantly improved the detection performance, with an AUC of 0.971 and an accuracy of 92.39%. Our results provide three new DNA methylation markers for BLCA and propose a urine-based DNA methylation detection panel for non-invasive clinical diagnosis.