Clinical Epigenetics最新文献

Background: To date, there is still a lack of studies focusing on the interactions between tobacco smoking, epigenetic modifications, and heart failure (HF) risk.

Methods: We first performed a prospective cohort study in the UK Biobank to assess the causal relationship between smoking behaviours and HF incidence. Subsequently, we applied two-sample Mendelian Randomization (MR) and epigenetic MR to further investigate the causal effects of smoking behaviours and related DNA methylation on HF, including its subtypes: heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF).

Results: In the UK Biobank cohort, former, ever, and current smoking were all associated with a higher risk of HF, with a clear dose-response relationship observed for pack-years of smoking. Additionally, earlier smoking cessation was linked to a lower risk of HF. Two-sample MR validated these observational findings and further identified the harmful effects of smoking behaviours on both HFpEF and HFrEF. In the epigenetic MR analysis, we found that DNA methylation alteration at cg15234271 [HPN] was associated with a reduced risk of HF, whereas cg16071219 [LPAR6], cg19593285 [E2F1], and cg01305745 [VKORC1] were linked to an elevated risk. For HF subtypes, cg26161820 [PPP1R1B] and cg26716839 [UNC119B] were associated with a lowered risk of HFrEF, while cg08548559 [PIK3IP1] was linked to an increased risk of HFpEF.

Conclusion: Our study demonstrates associations between smoking behaviours, related DNA methylation, and HF incidence, offering novel insights into the pathogenesis of HF.

Meiosis is a specialized cell division producing haploid gametes from diploid germ cells and is vital to sexual reproduction in mammals. This process entails carefully regulated molecular events including double-strand break repair, remodeling of the chromatin and the segregation of the chromosomes. There have been significant advances in understanding the core mechanisms through genetics and imaging techniques. Nevertheless, studying human meiosis is still difficult owing to limited access to tissue and interspecies differences in models using animals. Pluripotent stem cells (PSCs), namely embryonic and induced pluripotent stem cells, have turned out to be new in vitro models to model early germ cell development and meiotic progress in recent times. This article outlines the molecular regulation of meiosis in mammals and discusses the way in which the use of PSC-based models has begun to supplement classical methodologies in the study of meiosis.

Objective: To explore the association between life's essential 8 and epigenetic age based on twins population.

Methods: This study included 1030 twins (515 pairs) for cross-sectional analysis and conducted cross-lagged analysis among 294 twins (147 pairs) who participated in both the baseline and follow-up surveys from the Chinese National Twin Registry. LE8 scores were obtained from measurements based on American Heart Association definitions. DNA methylation data were used to calculate epigenetic age metrics, including GrimAA, DamAA and DunedinPACE. Linear mixed-effect models were applied for cross-twin analyses and within-monozygotic-pair analyses.

Results: In the cross-sectional analysis, higher LE8 score was associated with slower epigenetic aging (DunedinPACE and DamAA) in both across-twin analyses and within-monozygotic-pair analyses. In stratified analyses, the association between LE8 score and epigenetic age appeared more significant in males and in individuals aged 50 years older. The cross-lagged analysis further revealed significant temporal associations between LE8, health factor, and DunedinPACE.

Conclusion: Higher LE8 scores were associated with a deceleration in biological aging.

Background: DNA methylation plays an important role in systemic lupus erythematosus (SLE) pathogenesis by regulating immune cell function and disease progression. Dietary factors, particularly methyl-donor micronutrients such as folic acid and vitamin B12, may influence DNA methylation patterns and autoimmune responses. However, their specific effects in SLE, especially in adipose tissue that is a key modulator of systemic inflammation, remain unclear. Given the high prevalence of obesity in SLE and its impact on disease severity, understanding the interaction between nutritional status, epigenetics, and immune dysregulation is crucial. This study examines whether folic acid and vitamin B12 supplementation modulate adipose tissue DNA methylation in female SLE patients, considering their nutritional status, to uncover potential mechanisms influencing disease progression and therapeutic response. This is a randomized, double-blind, placebo-controlled trial with premenopausal women with inactive SLE, classified as normal weight (NW, n = 23) or excess body weight (EBW, n = 27). Participants received daily supplementation of folic acid (400 mcg) and vitamin B12 (2000 mcg) or placebo for 12 weeks. Phenotypic characteristics and adipose tissue DNA methylation profiles were assessed before and after intervention using the Illumina EPIC BeadChip platform.

Results: Supplementation significantly increased serum folic acid and vitamin B12 levels in both groups (p < 0.05), with a greater rise observed in NW patients (p = 0.035). In the NW group, 120 differentially methylated CpG sites (DMCpGs) were identified post-intervention (74 hypermethylated and 46 hypomethylated sites). These genes were linked to autoimmunity, inflammatory metabolism, obesity, and metabolic health pathways. In contrast, no DMCpGs were detected in the EBW group, potentially due to obesity-related chronic inflammation or altered folic acid metabolism associated with excessive adipose tissue.

Conclusion: Folic acid and vitamin B12 supplementation modulated DNA methylation in SLE depending on nutritional status. Epigenetic remodeling occurred exclusively in NW patients, whereas EBW patients showed no detectable changes. These findings suggest that obesity may create an "epigenetic resistance" to micronutrient interventions, highlighting the importance of precision nutrition strategies in autoimmune disease management.

Trial registration: NCT05097365.

Background: To identify blood DNA methylation profiles related to liver steatosis, we performed an EWAS on the presence of ultrasonically-identified liver steatosis in the Young Finns Study (YFS) participants (n = 1529, 33-50y.), and on liver enzyme levels and fatty liver index (FLI) across three discovery cohorts: YFS, LURIC (n = 2371, 17-92y.) and KORA FF4 (n = 1872, 39-88y.). We further investigated the discovered associations across the longitudinal subset of YFS (n = 255), encompassing three follow-ups over 32 years, and the three-generational YFS-3G follow-up in 2018-2020. Finally, we examined the associations of the discovered CpGs with nearby genetic variation and whole blood expression of nearby genes.

Results: In YFS, the methylation levels of cg06690548 (SLC7A11) were lower in individuals with liver steatosis (Δbeta = - 0.011, FDR = 0.004). Methylation of 9 CpGs associated with GGT and 23 CpGs with FLI in at least two of the discovery cohorts. Methylation at cg06690548 (SLC7A11) and the majority of the CpGs associating with GGT or FLI had the strongest association in the two oldest generations of YFS-3G follow-up (ages 43-59y. and 59-93y.), with minor or non-significant association in the youngest generation (ages 6-36y.). Discovered meQTLs for the CpGs did not modulate the association between the methylation levels and GGT or FLI. The expression of the nearby genes mediated only the association between cg06500161 (ABCG1) and cg20544516 (SREBF1) and FLI.

Conclusions: Our findings highlight the association between the methylation levels of cg06690548 (SLC7A11) and liver steatosis, describe the dynamic relationship between whole blood DNA methylation and MASLD, and contribute to a deeper understanding of the pathophysiology of liver diseases.

In recent years, it has been demonstrated that many of the pervasive genetic defects throughout cancerogenesis occur in genes encoding chromatin regulators (CRs). We analyzed the distribution and characteristics of well-studied CRs across tens of thousands of tumor samples. Our analysis revealed that tumors with mutations in CRs are associated with high tumor mutational burden (TMB). The co-occurrence of mutations in multiple CRs was linked with a further increase in TMB. Given that TMB may predict the clinical response to immune checkpoint inhibitor (ICI) treatment, we investigated the relationship between mutations in CRs and ICI response. We found that patients harboring mutations in CRs exhibited improved responses to ICI treatment, comparable to those with deficiencies in canonical DNA repair pathways. Overall, this study uncovered significant relationships between mutations in chromatin regulators and critical features of cancer, underscoring the need for further functional and clinical studies.

Background: Recurrent pregnancy loss (RPL) affects fertility problems in approximately 5% of couples, while the cause of RPL remains unknown in about half RPL cases, which is also called unexplained RPL. The male factors were associated with RPL in male partners, including chromosome abnormality and sperm DNA fragmentation. DNA methylation is one of the most extensively studied epigenetic factors that could help elucidate the mechanism underlying RPL in male partners.

Results: We revealed DNA methylation alternations occurring in sperm of RPL partners compared with the controls by genome-wide DNA methylation beadchip, including a series of differentially methylated CpG positions and genes. Importantly, we validated that the CpG site cg17985533 and the region chr11:1997780-1,997,899 from the H19 imprinted maternally expressed transcript were significantly hypermethylated in sperm of RPL-related men with > 10% mean methylation difference by targeted bisulfite sequencing. Moreover, the receiver operating characteristic analysis showed that CpG site cg17985533 and region chr11:1997780-1,997,899 could distinguish RPL-related men from controls, with an area under the curve of 0.7838 and 0.8125, sensitivity of 80% and 80%, and specificity of 80% and 75%, respectively. These results indicated that they could be potential biomarker for diagnosis of RPL in male partners.

Conclusions: This study highlighted the importance of H19 gene methylation in differentiating RPL-related men and control, and provided new insight for revealing potential epigenetic mechanisms for RPL in male partners.

Background: DNA methylation age, referred to as 'epigenetic age, epiAge' is an accurate biomarker for aging, including cancer. As a well established age-associated disease, colorectal cancer (CRC) is a highly heterogeneous cancer and can be divided into left-sided colon cancer (LCC), right-sided colon cancer (RCC) and rectal cancer according to the anatomical location of the tumor. However, the association of epigenetic age acceleration (EAA) with CRC tumor location, clinical characteristics, and patient outcomes remain to be clarified.

Methods: A total of 548 samples were collected for epiAge estimation, including 192 samples consisting of 96 CRC tumors and 96 matched normal tissues from GSE77718 and 356 CRC tumors from The Cancer Genome Atlas (TCGA). EpiAge were computed using four different epiAge models (Horvath2013, PhenoAge, ZhangQ2019, and EpiTOC). EpiAge and EAA were compared between LCC and RCC. Log rank test was used to assess the association of EAA with LCC and RCC survival.

Results: A significantly older epiAge in the RCC than LCC was observed (P = 0.00025) but not in normal colon tissues. In addition, compared with LCC, EAA was enhanced in female and microsatellite instability-high RCC samples. Meanwhile, we found that epiAge decreased continuously from RCC stage I to stage IV. In contrast, in LCC, stage I had the most serious epiAge deceleration (stage I: - 8.9; stage II: - 1.71; stage III: - 4.91; stage IV: - 4.67). Further, EAA is significantly and negatively or positively associated with RCC and LCC mortality, respectively.

Conclusions: Overall, our results suggest that EAA may be a useful biomarker for gaining a deeper understanding of CRC high heterogeneity from a biological aging perspective and will facilitate prognostic judgement and targeted treatments.

Background: Women with depression are less likely to breastfeed and experience more breastfeeding challenges. Potential biological mechanisms that link maternal depression with poor breastfeeding outcomes have not been investigated. This study examined associations between lifetime history of depression (LHD), prenatal oxytocin receptor gene (OXTR) DNA methylation, and breastfeeding outcomes.

Results: Longitudinal observational data from the Norwegian Mother, Father and Child Cohort Study (MoBa) were analysed (N = 3607). LHD was self-reported during pregnancy (week 15). Blood samples were collected at 16-18 weeks of pregnancy, and DNA methylation was measured using the Illumina Methylation EPIC BeadChip 850 K array. This array includes 22 CpG sites on the OXTR gene, which were used in analyses. Mothers self-reported breastfeeding initiation (breastmilk given to child in first month), breastfeeding maintenance (breastmilk given to child for 6 months or more) and breastfeeding problems. Maternal LHD was not associated with OXTR DNA methylation. There was some evidence that prenatal OXTR DNA methylation was associated with breastfeeding outcomes. There was an association between CpG cg26455676 and breastfeeding maintenance to 6 months (odds ratio = 1.59, 95% confidence intervals = 1.11-2.27, raw p = 0.01, adjusted p = 0.04). Higher levels of DNA methylation at CpG cg26455676 was associated with a greater likelihood of maintaining breastfeeding to 6 months.

Conclusions: This highly novel study highlights the intriguing possibility that maternal prenatal DNA methylation at genes important for breastfeeding may be associated with breastfeeding experiences. Further understanding of vastly differing breastfeeding experiences would assist with the targeting efforts to support breastfeeding women, particularly those who are vulnerable, such as mothers who have depression.

Background: Epigenetic alterations, particularly DNA methylation, and dysregulation of the tumor immune microenvironment (TIME) are increasingly recognized as critical factors in esophageal squamous cell carcinoma (ESCC) pathogenesis. Understanding the dynamic interplay between DNA methylation changes and TIME evolution during ESCC progression remains essential. We established a 4-nitroquinoline 1-oxide (4NQO)-induced ESCC mouse model, capturing distinct pathological stages: normal esophageal epithelium (Normal), esophageal simple hyperplasia (ESSH), intraepithelial neoplasia (IEN), and ESCC. Genome-wide DNA methylation profiling was performed using the Infinium Mouse Methylation BeadChip (285 K), coupled with transcriptome analysis via bulk RNA sequencing (RNA-seq). Immunohistochemistry (IHC) for Cd45 (leukocyte common antigen) validated immune cell infiltration.

Results: DNA methylation profiling revealed progressive genome-wide hypomethylation during ESCC development, with hypomethylated probes significantly enriched in immune response pathways. Notably, ESSH exhibited a methylation profile similar to IEN and ESCC. RNA-seq identified escalating numbers of differentially expressed genes (DEGs). Immune deconvolution analysis and IHC of Cd45 demonstrated dynamic changes in TIME composition from ESSH onwards. Furthermore, dynamic expression clustering identified an innate immune response-related gene cluster highly expressed in ESSH. Integrative analysis yielded 495 methylated regulatory genes, significantly enriched in leukocyte cell-cell adhesion and T cell activation pathways (e.g., Ptprc/Cd45, Il12rb1, Tox), with peak activity in ESSH.

Conclusions: These findings highlight ESSH as a critical window where epigenetically driven immune changes facilitate ESCC progression. Targeting these early epigenetic-immune interactions may offer a novel strategy for ESCC early detection and combination therapy.