Clinical Epigenetics最新文献

Background: DNA methylation profiling has emerged as a promising tool for improving pathological diagnosis. This study investigates the diagnostic efficacy and subgroup heterogeneity of SHOX2, RASSF1A, Septin9, and HOXA9 methylation in pleural effusion lymphoma, aiming to enhance diagnostic accuracy and identify high-risk molecular subgroups.

Methods: A cohort of 109 patients (73 lymphoma, 36 benign pleural effusions) was analyzed using quantitative methylation-specific PCR for the four biomarkers. Receiver operating characteristic (ROC) curves were constructed to determine optimal cutoff values for each marker, and their diagnostic performance was evaluated in different lymphoma subgroups.

Results: The cycle threshold values for the internal control β-actin predominantly ranged from 18 to 23, suggesting consistent DNA input for methylation analysis. ROC curve revealed that the area under the curve (AUC) values were 0.871 (SHOX2), 0.779 (HOXA9), 0.611 (Septin9), and 0.548 (RASSF1A). When combined, the four markers achieved an AUC of 0.896, with an overall diagnostic sensitivity of 83.6% and a specificity of 94.4%. SHOX2 and HOXA9 demonstrated higher sensitivity within diffuse large B-cell lymphoma (DLBCL) subgroups, with SHOX2 achieving 100% sensitivity in the non-GCB subgroup and HOXA9 achieving 90.9% sensitivity in the GCB subgroup. Septin9 methylation was significantly associated with the presence of B symptoms (P = 0.041). Importantly, RASSF1A methylation was more strongly associated with TP53 deletion rather than with Bcl-2/IGH, Bcl-6, or c-MYC rearrangements.

Conclusion: Integrating methylation markers SHOX2, HOXA9, Septin9, and RASSF1A exhibits significant diagnostic potential in pleural effusion lymphoma, especially within DLBCL subgroups. These markers could prove valuable in identifying high-risk subgroups and guiding clinical decision-making.

Background: The Helsmoortel-Van der Aa syndrome is an autosomal-dominant neurodevelopment disorder caused by heterozygous de novo variants in the Activity-Dependent Neuroprotective Protein (ADNP) gene, characterized by autism, intellectual disability, dysmorphic facial features, and deficits in multiple organ systems. ADNP is a zinc finger DNA-binding protein that primarily interacts with chromatin remodelers regulating embryonic development, while also associating with components of the cytoskeleton, thereby regulating autophagy and microtubule dynamics during development. In this study, we investigated these nucleocytoskeletal alterations explaining neurodevelopmental delay in a child with Helsmoortel-Van der Aa syndrome who had an unaffected dizygotic twin brother.

Results: We performed a genome-wide methylation array on PBMCs from dizygotic twins, showing a predominant CpG hypomethylation episignature. Enrichment analysis of methylated genes revealed significant pathway changes in actin filament organization, Wnt signaling, embryonic development, heart development, and the immune system. In addition, transcriptome sequencing substantiated the affected pathways regulating nuclear and cytoskeletal filamentous alterations associated with autism and neurodevelopmental delay. Brain magnetic resonance imaging showed a mild generalized prominence of the subarachnoid space overlying both hemispheres, revealing intricate patterns of neurodevelopmental delay.

Conclusions: We report the first molecular study performed on dizygotic twins of which one was diagnosed with Helsmoortel-Van der Aa syndrome, revealing Wnt signaling and filamentous cytoskeletal alterations as a potential drug targets for therapy.

Limitations: Indications for neurodegeneration, following these cytoskeletal perturbations, have been observed in cellular and murine models for the Helsmoortel-Van der Aa syndrome. However, clinical evidence remains unclear due to the young age of patients, limiting long-term studies on the aging brain. Further longitudinal imaging studies combined with histopathological autopsy sections are required to study the impact of an ADNP variant in the brain as patients come to age.

Background: Early-life psychosocial stress is increasingly recognized as a contributor to accelerated biological aging and health disparities, yet its impact during young adulthood remains underexplored. Existing studies often focus on one or two dimensions of stress exposure and rely on retrospective assessments. Utilizing data from a longitudinal cohort initiated in 1989, we aim to examine the impact of early life psychosocial stress on accelerated aging in young adulthood, as well as its potential contribution to health disparities between Black and White Americans. Participants included 470 individuals (223 Black and 247 White Americans) with DNA samples collected at age > 20 years. Psychosocial stress exposures in the first 20 years of life were assessed prospectively using validated instruments across individual, family, and neighborhood domains. DunedinPACE, a novel biomarker of the pace of aging, was calculated from DNA methylation data generated from peripheral blood using the Illumina 450K array. The joint effect of early life psychosocial factors on DunedinPACE and the relative importance of each stressor were estimated using the Weighted Quantile Sum (WQS) approach. Mediation analysis was conducted to evaluate the contribution of early life stress to racial disparities in aging.

Results: Compared to White Americans, Black Americans reported higher overall levels of early life stress (mean = 1.52 vs. 1.38, adjusted p = 0.002) and exhibited a faster pace of aging in young adulthood (DunedinPACE score mean = 0.98 vs. 0.93, adjusted p < 0.001). WQS analysis revealed a positive joint effect of early life psychosocial stress on DunedinPACE (β = 0.25, 95% CI: 0.159-0.335), with the top four contributors being parental socioeconomic status, family emotional expression, peer pressure, and neighborhood safety conditions. Mediation analysis indicated that early-life stress accounted for 22% of the racial disparity in biological aging (p = .01).

Conclusion: Our findings suggest that exposure to disadvantaged psychosocial environments in early life is associated with accelerated biological aging in young adulthood. Racial differences in stress exposure partially explain disparities in aging, underscoring the importance of early interventions to reduce health disparities across the life course.

Background: Episignatures are disease-specific, genome-wide DNA methylation patterns identified in more than 100 genetic syndromes caused by mutation of genes related to epigenetic modifiers. The utility of episignatures as a disease diagnostic tool has been demonstrated in recent years. However, studies evaluating episignatures in imprinting disorders (IDs) are very limited. We hypothesized that identifying episignatures in Silver-Russell syndrome (SRS), one of the representative IDs, could lead to the development of a new diagnostic tool for SRS. We investigated methylation profiles in patients with different molecular etiologies to clarify the presence or absence of DNA methylation episignatures in SRS.

Results: We conducted genome-wide methylation analysis (GWMA) using the HumanMethylationEPIC array in 27 patients consisting of five groups based on molecular etiologies satisfying clinical diagnostic criteria: hypomethylation of H19-differentially methylated region (DMR) (n = 9), maternal uniparental disomy chromosome 7 (n = 11), IGF2 variant (n = 3), PLAG1 variant (n = 2), and deletions including KCNQ1OT1:TSS-DMR (n = 2). We compared the methylation levels of CpGs (β values) between each group and control group (94 pediatric samples) and extracted aberrantly methylated CpGs satisfying the following criteria: (1) Bonferroni-corrected p value < 0.05, and (2) the absolute value of ∆β (|∆β|), the difference between the average β value of each ID group and controls at each probe, was above 0.1. Based on the extracted aberrantly methylated CpGs, we examined (1) aberrantly methylated patterns, (2) aberrantly methylated regions, and 3) CpG-enriched genes and their functions, shared by multiple groups. Although several CpGs were commonly hypermethylated or hypomethylated in two of the five groups, the number of CpGs was too small to form characteristic methylation patterns. Several aberrantly methylated regions, including disease-responsible DMRs of SRS, were identified in each group, but no regions common in multiple groups were identified. Previously reported aberrantly methylated regions other than disease-responsible DMRs were not identified. In addition, we found no CpG-enriched genes or their functions common in multiple groups.

Conclusions: GWMA in SRS patients with different molecular etiologies identified no characteristic episignatures. Only methylation changes of CpGs within disease-responsible DMRs, not genome-wide methylation changes, occur in some SRS etiologies.

Background: Constitutional primary monoallelic promoter methylation of hereditary cancer genes, although rare, may explain early-onset cancers without family history. Also, promoter methylation of a hereditary cancer gene secondary to a genetic alteration in a methylation regulatory region can cause a hereditary cancer syndrome. This study investigates constitutional promoter methylation as mechanism of inactivation of cancer predisposition genes in genetically unsolved familial and/or early-onset colorectal cancer (CRC) patients.

Results: Bisulfite-treated peripheral blood DNA from 46 early-onset/familial CRC patients was analyzed using the Illumina Infinium MethylationEPIC BeadChip. One early-onset CRC patient exhibited constitutional, likely monoallelic, methylation of CpG island 102 in LTBP4, a gene involved in TGF-β signaling. Somatic methylation of this CpG island is common in CRC, and correlates with LTBP4 downregulation. LTBP4 double knockout mice develop colorectal adenomas and carcinomas, supporting the role of this gene in CRC predisposition. No additional cases with constitutional LTBP4 CpG island 102 methylation or enrichment of deleterious LTBP4 variants in CRC patients compared to controls were found. Another early-onset CRC patient exhibited mosaic BRCA1 promoter methylation, typically associated with increased breast and ovarian cancer risk. No somatic second hit in BRCA1 was detected in the patient's tumor, and homologous recombination deficiency-associated features were inconclusive.

Conclusions: Our findings suggest that constitutional methylation of LTBP4 CpG island 102 may be associated with increased CRC risk. Identification of additional cases is needed to confirm the existence of a novel CRC predisposition syndrome driven by epigenetic inactivation of LTBP4, potentially also linked to other clinical phenotypes associated with LTBP4 deficiency, such as pulmonary emphysema. Whether constitutional BRCA1 methylation contributes to CRC risk remains to be determined.

Autoimmune skin diseases (AISDs) are disorders characterized by disrupted immune tolerance and aberrant responses against skin antigens, including atopic dermatitis (AD), psoriasis, systemic lupus erythematosus (SLE), bullous pemphigoid (BP), and other common conditions. Dysregulated expression of immune-related genes-particularly those governing B and T cell functions-holds promise as diagnostic and prognostic biomarkers, though their regulatory mechanisms remain incompletely defined. This review systematically synthesizes recent evidence elucidating the central role of three core epigenetic mechanisms-DNA methylation, histone modifications (including emerging metabolically linked alterations), and noncoding RNAs (ncRNAs)-in driving AISD pathogenesis. We highlight the dynamic interplay between epigenetic dysregulation, immune dysfunction, and skin barrier impairment. Deciphering these epigenetic networks and identifying key regulators (e.g., DNMTs, histone-modifying enzymes, ncRNAs) may enable high-precision diagnostics and novel therapies to restore immune homeostasis. Such advances will deepen mechanistic insights and transform clinical management paradigms.

Background: Epigenetic alterations during fetal development have been proposed as key factors explaining associations between maternal lifestyle during pregnancy and later health outcomes in the offspring, pertaining to the developmental origin of health and disease hypothesis.

Objectives: To assess the association of maternal lifestyle with offsprings' birth weight and underlying epigenetic mediatory mechanisms in the NorthPop prospective birth cohort.

Methods: A three-step analytic pipeline was applied. In 722 mother-child pairs, overall associations between ten maternal lifestyle factors and the offspring's standardized birth weight were first evaluated by multiple linear regression. Three high-dimensional mediation methods, based on sure independence screening and penalized regression, were then applied on the beta methylation matrix to identify candidate CpG mediators in cord blood driving the significant overall associations. Finally, robust and ordinary least squares (OLS) regression-based classical mediation methods were used with candidate CpG probes to assess single- and multiple (parallel and serial)-mediator models on a low-dimensional space.

Results: Gestational weight gain (GWG) (β-adj = 0.03; p = 2 × 10^-5) and maternal BMI at the beginning of pregnancy (β-adj = 0.036; p = 1 × 10^-4) were significantly associated with the offspring's standardized birth weight. High-dimensional mediation analyses identified pooled sets of four (cg19242268 [TCEA2]; cg08461903 [N/A]; cg14798382 [CHERP/C19orf44] and cg21516291 [SLC35C2]) and five (cg17040807 [CYGB]; cg19242268 [TCEA2]; cg26552621 [CIRBP]; cg04457572 [CDH23] and cg06457011 [PLCG1]) candidate CpG mediators related to GWG and BMI at the beginning of pregnancy, respectively. For both exposures, classical mediation analyses revealed a range of significant single- and multiple (both serial and parallel)-mediator models via both robust and OLS regression based approaches. These indicated the likely presence of individual, causally linked multiple, and causally independent multiple mediatory pathways underlying the two significant overall associations.

Conclusions: Our findings support the hypothesis that neonatal health effects related to maternal lifestyle may be partly mediated by epigenetic alterations. Findings also suggest the possible involvement of multiple DNA methylation sites via various mediatory pathways.

Background: Iron homeostasis is essential for fundamental biological processes, yet its impact on epigenetic aging and mortality remains poorly understood. This study aimed to investigate associations between dietary iron intake and DNA methylation (DNAm) aging markers and to determine whether these epigenetic signatures mediate iron's effects on mortality outcomes.

Methods: We analyzed data from 2,398 adults aged ≥ 50 years in the National Health and Nutrition Examination Survey (1999-2002) with up to 20 years of mortality follow-up. Dietary iron intake was assessed through 24-h recall interviews. DNA methylation was profiled using the Illumina Infinium MethylationEPIC BeadChip. We employed multiple linear regression to identify iron-responsive DNAm features, Cox proportional hazards models to assess mortality associations, and formal mediation analyses to quantify epigenetic pathways.

Results: Higher dietary iron intake was significantly associated with favorable epigenetic profiles, particularly with reduced levels of mortality-predictive DNAm markers GrimAge2Mort (β = -0.079, FDR = 0.00022), CRPMort (β = -0.072, FDR = 0.0037), and B2MMort (β = -0.057, FDR = 0.042). These iron-responsive DNAm features strongly predicted all-cause mortality (HRs per SD increase: 1.34, 1.21, and 1.08, respectively; all p < 0.05) and cause-specific mortality. Higher iron intake was directly associated with reduced risk of all-cause mortality (HR = 0.93 per SD increase, 95% CI 0.87-0.99), heart disease mortality (HR = 0.87, 95% CI 0.78-0.97), and respiratory disease mortality (HR = 0.72, 95% CI 0.56-0.93). Mediation analyses revealed that GrimAge2Mort mediated 22.7% of iron's protective effect on all-cause mortality and 14.7% on heart disease mortality.

Conclusions: This study establishes dietary iron as a modifiable determinant of epigenetic aging and mortality risk in older adults, with epigenetic recalibration mediating a substantial proportion of iron's protective effects. These findings suggest optimizing iron intake may represent a promising nutritional strategy to promote healthy aging.

Abdominal aortic aneurysm (AAA) is a progressive vascular disorder closely associated with the phenotypic transformation of vascular smooth muscle cells (VSMCs). Histone modifications-including acetylation, methylation, phosphorylation, lactylation, succinylation, ubiquitination, and small ubiquitin-like modifier modification-play pivotal roles in regulating chromatin accessibility, gene expression, and cellular behavior during this transformation. These epigenetic marks influence VSMCs proliferation, migration, apoptosis, and inflammatory responses, thereby contributing to AAA development and progression. This review systematically summarizes the molecular mechanisms by which histone modifications regulate VSMCs phenotypes and explores emerging therapeutic strategies that target epigenetic regulators such as histone deacetylases, histone methyltransferases, and lactate dehydrogenase A. Furthermore, this study highlights the potential of spatial omics and CRISPR-dCas9 epigenome editing tools for deciphering and modulating VSMC states with spatial and cell type precision. Advancing our understanding of these regulatory networks may pave the way for novel, individualized interventions in AAA treatment.

Background: NOP2/Sun RNA methyltransferase family member 2 (NSUN2) catalyzes 5-methylcytosine (m⁵C) modifications in tRNA, rRNA, and mRNA, playing critical roles in various malignancies. However, its expression and functional relevance in B-acute lymphoblastic leukemia (B-ALL) remain largely undefined.

Methods: Lineage-negative progenitor cells from Nsun2 knockout (Δ/Δ) and wild-type (fl/fl) mice were used to generate BCR-ABL (P190)-driven murine B-ALL model. Furthermore, RNA sequencing (RNA-seq) was performed to identify NSUN2 targets. Cell proliferation, apoptosis, and colony formation, and global protein synthesis were measured in B-ALL cells with NSUN2 deficiency.

Results: Here, we found that NSUN2 expression was significantly higher in bone marrow (BM) cells from B-ALL patients than normal controls (NCs). Knockdown of NSUN2 reduced m⁵C amounts and induced ferroptosis and apoptosis in B-ALL cells. Moreover, Nsun2 knockout significantly suppressed the leukemic burden and extended the OS in the murine B-ALL model in vivo. RNA-seq and subsequent studies identified ferritin heavy chain 1 (FTH1) as a downstream target of NSUN2. NSUN2 depletion sensitized B-ALL cells to ferroptosis induction via inhibiting FTH1 expression. In addition, overexpression of FTH1 rescued the ferroptosis and apoptosis induced by NSUN2 knockdown. Mechanistically, NSUN2 knockdown reduced m⁵C modifications on 3'UTR of FTH1 mRNA, impairing its stability and reducing FTH1 expression. Overexpression of wild-type (WT) NSUN2, but not its mutants, blocked NSUN2 knockdown-induced cytotoxic effects, indicating that NSUN2 enhances leukemogenesis in an m⁵C-dependent manner. In addition, NSUN2 deficiency inhibited global protein synthesis in both human and murine B-ALL cells. In contrast, Nsun2 depletion had a minimal impact on ferroptosis and protein synthesis in murine pre-B (B220⁺) cells, suggesting selective leukemic dependency.

Conclusions: Our results demonstrate that NSUN2 facilitates leukemogenesis by increasing FTH1 expression and enhancing global protein synthesis in an m⁵C-dependent manner. Targeting NSUN2 might provide a promising therapeutic strategy for B-ALL.