Epigenetics最新文献

Some benign and malignant breast tumours are similar in pathological morphology, which are difficult to be distinguished in clinical diagnosis. In this study, we intended to explore novel biomarkers for differential diagnosis of benign and malignant breast tumours. Methylation EPIC 850K beadchip and RNA-sequencing were used to analyse 29 tissue samples from patients with early-stage breast cancer (BC) and benign breast tumours for differently methylated and expressed genes. The altered methylation of IL21R was semi-quantitatively validated in an independent study with 566 tissue samples (279 BC vs. 287 benign breast tumours) using mass spectrometry. Binary logistic regression analysis was performed to evaluate the association between IL21R methylation and BC. BC-associated IL21R hypomethylation and overexpression were identified in the discovery round. In the validation round, BC patients presented significant IL21R hypomethylation compared to women with benign breast tumours (ORs ≥1.29 per-10% methylation, p-values ≤ 5.69E-14), and this hypomethylation was even enhanced in BC patients with ER-negative and PR-negative tumours as well as with triple-negative tumours. The methylation of IL21R showed efficient discriminatory power to distinguish benign breast tumours from BC (area under curve (AUC) = 0.88), and especially from ER-negative BC (AUC = 0.95), PR-negative BC (AUC = 0.93) and triple-negative BC (AUC = 0.96). We disclosed significant IL21R hypomethylation in patients with BC compared to women with benign breast tumours, and revealed the somatic change of DNA methylation could be a potential biomarker for molecular pathology of BC.

Changes in leukocyte populations may confound the disease-associated miRNA signals in the blood of cancer patients. We aimed to develop a method to detect differentially expressed miRNAs from lung cancer whole blood samples that are not influenced by variations in leukocyte proportions. The Ref-miREO method identifies differential miRNAs unaffected by changes in leukocyte populations by comparing the within-sample relative expression orderings (REOs) of miRNAs from healthy leukocyte subtypes and those from lung cancer blood samples. Over 77% of the differential miRNAs observed between lung cancer and healthy blood samples overlapped with those between myeloid-derived and lymphoid-derived leukocytes, suggesting the potential impact of changes in leukocyte populations on miRNA profile. Ref-miREO identified 16 differential miRNAs that target 19 lung adenocarcinoma-related genes previously linked to leukocytes. These miRNAs showed enrichment in cancer-related pathways and demonstrated high potential as diagnostic biomarkers, with the LASSO regression models effectively distinguishing between healthy and lung cancer blood or serum samples (all AUC > 0.85). Additionally, 12 of these miRNAs exhibited significant prognostic correlations. The Ref-miREO method offers valuable candidates for circulating biomarker detection in cancer that are not affected by changes in leukocyte populations.

N6 methyladenosine (m6A), methylation at the sixth N atom of adenosine, is the most common and abundant modification in mammalian mRNAs and non-coding RNAs. Increasing evidence shows that the alteration of m6A modification level could regulate tumour proliferation, metastasis, self-renewal, and immune infiltration by regulating the related expression of tumour genes. However, the role of m6A modification in colorectal cancer (CRC) drug resistance is unclear. Here, MeRIP-seq and RNA-seq techniques were utilized to obtain mRNA, lncRNA expression, and their methylation profiles in 5-Fluorouracil (5-FU)-resistant colon cancer HCT-15 cells and control cells. In addition, we performed detailed bioinformatics analysis as well as in vitro experiments of lncRNA to explore the function of lncRNA with differential m6A in CRC progression and drug resistance. In this study, we obtained the m6A methylomic landscape of CRC cells and resistance group cells by MeRIP-seq and RNA-seq. We identified 3698 differential m6A peaks, of which 2224 were hypermethylated, and 1474 were hypomethylated. Among the lncRNAs, 60 were hypermethylated, and 38 were hypomethylated. GO and KEGG analysis annotations showed significant enrichment of endocytosis and MAPK signalling pathways. Moreover, knockdown of lncRNA ADIRF-AS1 and AL139035.1 promoted CRC proliferation and invasive metastasis in vitro. lncRNA- mRNA network showed that ADIRF-AS1 and AL139035.1 May play a key role in regulating drug resistance formation. We provide the first m6A methylation profile in 5-FU resistance CRC cells and analyse the functions of differential m6A-modified mRNAs and lncRNAs. Our results indicated that differential m6A RNAs were significantly associated with MAPK signalling and endocytosis after induction of 5-FU resistance. Knockdown of LncRNA ADIRF-AS1 and AL139035.1 promotes CRC progression and might be critical in regulating drug resistance formation.

Cytomegalovirus (CMV) infection and reactivation in solid organ transplant (SOT) recipients increases the risk of viremia, graft failure and death. Clinical studies of CMV serostatus indicate that donor positive recipient negative (D⁺/R^-) patients have greater viremia risk than D^-/R^-. The majority of patients are R⁺ having intermediate serologic risk. To characterize the long-term impact of CMV infection and assess viremia risk, we sought to measure the effects of CMV on the recipient immune epigenome. Specifically, we profiled DNA methylation in 156 individuals before lung or kidney transplant. We found that the methylome of CMV positive SOT recipients is hyper-methylated at loci associated with neural development and Polycomb group (PcG) protein binding, and hypo-methylated at regions critical for the maturation of lymphocytes. In addition, we developed a machine learning-based model to predict the recipient CMV serostatus after correcting for cell type composition and ancestry. This CMV episcore measured at baseline in R⁺ individual stratifies viremia risk accurately in the lung transplant cohort, and along with serostatus the CMV episcore could be a potential biomarker for identifying R⁺ patients at high viremia risk.

Cattle farming faces challenges linked to intensive exploitation and climate change, requiring the reinforcement of animal resilience in response to these dynamic environments. Currently, genetic selection is used to enhance resilience by identifying animals resistant to specific diseases; however, certain diseases, such as mastitis, pose difficulties in genetic prediction. This study introduced the utilization of enzymatic methyl sequencing (EM-seq) of the blood genomic DNA from twelve dairy cows to identify DNA methylation biomarkers, with the aim of predicting resilience and susceptibility to mastitis. The analysis uncovered significant differences between cows resilient and susceptible to mastitis, with 196,275 differentially methylated cytosines (DMCs) and 1,227 Differentially Methylated Regions (DMRs). Key genes associated with the immune response and morphological traits, including ENOPH1, MYL10 and KIR2DL5A, were identified by our analysis. Quantitative trait loci (QTL) were also highlighted and the body weight trait was the most targeted by DMCs and DMRs. Based on our results, the risk of developing mastitis can potentially be estimated with as few as fifty methylation biomarkers, paving the way for early animal selection. This research sets the stage for improved animal health management and economic yields within the framework of agricultural sustainability through early selection based on the epigenetic status of animals.

Eastern and Western Finns show a striking difference in coronary heart disease-related mortality; genetics is a known contributor for this discrepancy. Here, we discuss the potential role of DNA methylation in mediating the discrepancy in cardiometabolic disease-risk phenotypes between the sub-populations. We used data from the Young Finns Study (n = 969) to compare the genome-wide DNA methylation levels of East- and West-originating Finns. We identified 21 differentially methylated loci (FDR < 0.05; Δβ >2.5%) and 7 regions (smoothed FDR < 0.05; CpGs ≥ 5). Methylation at all loci and regions associates with genetic variants (p < 5 × 10^-8). Independently of genetics, methylation at 11 loci and 4 regions associates with transcript expression, including genes encoding zinc finger proteins. Similarly, methylation at 5 loci and 4 regions associates with cardiometabolic disease-risk phenotypes including triglycerides, glucose, cholesterol, as well as insulin treatment. This analysis was also performed in LURIC (n = 2371), a German cardiovascular patient cohort, and results replicated for the association of methylation at cg26740318 and DMR_11p15 with diabetes-related phenotypes and methylation at DMR_22q13 with triglyceride levels. Our results indicate that DNA methylation differences between East and West Finns may have a functional role in mediating the cardiometabolic disease discrepancy between the sub-populations.

Penile squamous cell carcinoma (SCC) is a rare and aggressive tumour mainly related to lifestyle behaviour and human papillomavirus (HPV) infection. Environmentally induced loss of imprinting (LOI) at the H19 differentially methylated region (H19DMR) is associated with many cancers in the early events of tumorigenesis and may be involved in the pathogenesis of penile SCC. We sought to evaluate the DNA methylation pattern at H19DMR and its association with HPV infection in men with penile SCC by bisulfite sequencing (bis-seq). We observed an average methylation of 32.2% ± 11.6% at the H19DMR of penile SCC and did not observe an association between the p16^INK4a+ (p = 0.59) and high-risk HPV+ (p = 0.338) markers with methylation level. The average methylation did not change according to HPV positive for p16^INK4a+ or hrHPV+ (35.4% ± 10%) and negative for both markers (32.4% ± 10.1%) groups. As the region analysed has a binding site for the CTCF protein, the hypomethylation at the surrounding CpG sites might alter its insulator function. In addition, there was a positive correlation between intense polymorphonuclear cell infiltration and hypomethylation at H19DMR (p = 0.035). Here, we report that hypomethylation at H19DMR in penile SCC might contribute to tumour progression and aggressiveness regardless of HPV infection.

Breast cancer is the most common cancer diagnosed in women and is often treated with chemotherapy. Although previous studies have demonstrated increasing biological age in patients who receive chemotherapy, evaluation of this association with DNA methylation-based markers of biological ageing may provide novel insight into the role of chemotherapy on the ageing process. We therefore sought to investigate the association between chemotherapy and markers of biological ageing as estimated from DNA methylation in women with breast cancer. DNA methylation profiling was performed on peripheral blood collected from 18 patients before and after the first cycle of chemotherapy using the Infinium HumanMethylation450 BeadChip. Six markers of biological age acceleration were estimated from DNA methylation levels. Multiple linear regression analyses were performed to evaluate the association between each metric of biological age acceleration and chemotherapy. After adjusting for chronological age and race, intrinsic epigenetic age acceleration (p = 0.041), extrinsic epigenetic age acceleration (p = 0.050), PhenoAge acceleration (p = 0.001), GrimAge acceleration (p < 0.001), and DunedinPACE (p = 0.006) were significantly higher and telomere length (p = 0.027) was significantly lower following the first cycle of chemotherapy compared to before treatment initiation. These results demonstrate greater biological ageing as estimated from DNA methylation following chemotherapy in women with breast cancer. Our findings illustrate that cytotoxic therapies may modulate the ageing process among breast cancer patients and may also have implications for age-related health conditions in cancer survivors.

Male infertility has been a primary cause of global infertility, affecting 8-12% of couples worldwide. Previous studies have shown that semen quality decreases with advanced aging with an increased presence of inflammatory cells. In this study, we examined changes in the epigenome across a diverse cohort that includes both fertile and infertile men. We also compare the age-associated changes in semen to those observed in buccal swabs in order to characterize differences in epigenetic aging across diverse tissues. We found that variations in the semen methylome associated with aging are linked to inflammatory genes. Many age-associated sites are demethylated with advanced aging and are associated with the activation of inflammatory pathways. By contrast, we do not observe age-associated changes in inflammatory genes in buccal swab methylomes, which instead are characterized by changes to bivalent promoters. Our findings highlight the potential of epigenetic markers as indicators of male reproductive health.

Idiopathic pulmonary fibrosis (IPF) is a progressive and life-threatening respiratory disease characterized by worsening lung function due to excessive scarring. The objective of this study was to investigate the role of the long non-coding RNA ANRIL (antisense non-coding RNA in the INK4 locus) in the development of IPF. Our research revealed a significant increase in ANRIL expression in pulmonary fibrosis, consistent with prior studies indicating elevated ANRIL levels in fibrotic tissues. In vitro experiments demonstrated that elevated ANRIL expression promoted fibroblast activation, as evidenced by the upregulation of fibrosis-related markers. Mechanistically, we found that ANRIL interacts with let-7d-5p, a microRNA involved in gene regulation, acting as a sponge for let-7d-5p. Functional experiments confirmed a potential influence of let-7d-5p on fibroblast activation through direct interaction with ANRIL. Furthermore, our investigation identified TGFBR1 as a potential mediator of ANRIL's fibrogenic effects. Silence of TGFBR1 mitigated the fibrotic phenotype induced by ANRIL overexpression. Collectively, these results suggest that ANRIL promotes fibroblast activation and fibrosis development, possibly through the let-7d-5p/TGFBR1 axis, indicating that ANRIL could be a potential therapeutic target for pulmonary fibrosis.