Epigenetics最新文献

DNA methylation is among the most promising biomarkers for age prediction, enabling the development of epigenetic clocks that correlate methylation profiles with chronological age. In this study, we investigated the relationship between ageing and disease susceptibility, focusing on both nuclear and mitochondrial DNA methylation in dairy cows. Genome-wide DNA methylation profiling was performed using enzymatic methyl-seq, covering 53 million CpG sites. The dataset included 96 cows with different phenotypes, sampled cross-sectionally and ranging from 2 to 9 years of age. We applied elastic net regression to identify the most predictive CpG sites for age estimation, achieving a mean absolute error of 111 days with a strong correlation to chronological age r = 0.97. Beyond chronological age prediction, we assessed the impact of disease status on epigenetic ageing. Our results revealed accelerated epigenetic ageing in cows susceptible to diseases, suggesting a link between health-related stress and disrupted DNA methylation dynamics. We further identified age-associated promoter methylation changes, particularly in MAB21L1, which may play a role in molecular ageing mechanisms. Additionally, we observed a decline in mitochondrial DNA methylation with age, notably in genes encoding Cytochrome c oxidase (COX), indicating a possible connection between mitochondrial dysfunction and epigenetic regulation. An inverse correlation between D-loop methylation and mtDNA copy number was also observed. This study demonstrates the potential of epigenetic models for biological age prediction in livestock, while recognizing that their accuracy may vary among species with different lifespans.

Although N⁶-methyladenosine (m⁶A) may be related to the pathogenesis of fibrotic process, the mechanism of m⁶A modification in aging-related idiopathic pulmonary fibrosis (IPF) remains unclear. Three-milliliter venous blood was collected from IPF patients and healthy controls. MeRIP-seq and RNA-seq were utilized to investigate differential m⁶A modification. The expressions of identified m⁶A regulator and target gene were validated using MeRIP-qPCR and real-time PCR. Moreover, we established an animal model and a senescent model of A549 cells to explore the associated molecular mechanism. Our study provided a panorama of m⁶A methylation in IPF. Increased peaks (3756) and decreased peaks (4712) were observed in the IPF group. The association analysis showed that 749 DEGs were affected by m⁶A methylation in IPF. Among the m⁶A regulators, the expression of METTL14 decreased in IPF. The m⁶A level of our interested gene DDIT4 decreased significantly, but the mRNA level of DDIT4 was higher in IPF. This was further verified in bleomycin-induced pulmonary fibrosis. At the cellular level, it was further confirmed that METTL14 and DDIT4 might participate in the senescence of alveolar epithelial cells. The downregulation of METTL14 might inhibit the decay of DDIT4 mRNA by reducing the m⁶A modification level of DDIT4 mRNA, leading to high expression of DDIT4 mRNA and protein. Our study provided a panorama of m⁶A alterations in IPF and discovered METTL14 as a potential intervention target for epigenetic modification in IPF. These results pave the way for future investigations regarding m⁶A modifications in aging-related IPF.

The incidence rate of breast cancer (BC) ranks first among female malignant tumors. Late-stage BC patients are at risk of death from distant metastasis. Circular RNAs (circRNAs) play an important function in cancer development. This study looked at the role of circMYH9 in BC. The nude mouse tumor-bearing experiment was used to verify the role of circMYH9 in regulating BC tumor growth in mice. Gene expression and protein amount were tested by qRT-PCR, western blot, and IHC. The pathological changes in tumor tissues were analyzed by HE staining. Cell viability, proliferation, migration, and invasion were assessed using CCK8, colony formation assay, wound healing assay, and Transwell assay, respectively. The interactions between circMYH9, SPAG6, and EIF4A3 were analyzed by RIP assay. CircMYH9 was significantly upregulated in BC, and its upregulated was related to poor prognosis. CircMYH9 silencing markedly impaired BC cell proliferation, migration, and invasion. Mechanistically, circMYH9 promoted the mRNA stability and expression of SPAG6 by recruiting EIF4A3. As expected, SPAG6 overexpression abrogated inhibition mediated by circMYH9 knockdown on BC cell malignant behaviors. In addition, circMYH9 knockdown inhibited PI3K/Akt signal pathway by increasing PTEN expression in BC cells, while was reversed by SPAG6 upregulation. PTEN inhibition abolished inhibition induced by circMYH9 downregulation on BC malignant progression. Moreover, circMYH9 silencing inhibited tumor growth in mice. CircMYH9 overexpression regulated the PTEN/PI3K/AKT pathway by increasing SPAG6 mRNA stability through recruiting EIF4A3, thereby promoting BC malignant progression.

Arginine methyltransferase 1 (PRMT1) is widely recognized as an oncogene in various cancers. However, its specific role and underlying mechanisms in hepatocellular carcinoma (HCC) remain insufficiently understood. This study investigated the function of PRMT1 in HCC development and immune evasion. A comprehensive approach combining database analysis (including TCGA, The Human Protein Atlas, Kaplan-Meier Plotter, and TIMER2.0), molecular techniques (such as RT-qPCR, Western blot analysis, and co-immunoprecipitation), cell-based assays (including MTT, colony formation, transwell, and T cell killing assays), and in vivo models was employed to explore PRMT1's role in HCC. The findings revealed a marked upregulation of PRMT1 in both HCC clinical samples and cell lines. Depletion of PRMT1 inhibited cell proliferation and immune evasion while reducing cell migration and invasion. Mechanistically, PRMT1 was shown to interact with MYC, facilitating its arginine methylation and enhancing its protein stability. Moreover, re-expression of MYC significantly reversed the anti-tumour effects associated with PRMT1 depletion. In vivo experiments further corroborated these results. Collectively, PRMT1 promotes HCC progression and immune escape by mediating ADMA methylation of MYC, thereby regulating its stability and expression.

A global priority for ameliorating male factor infertility includes identification of environmental factors and mechanisms that impact sperm function. Detection of endocrine disrupting chemicals (EDC) in seminal plasma and within the female reproductive tract has created an urgent need to understand how environmental stressors alter postejaculatory sperm function. Tributyltin chloride (TBT) is an EDC and epigenetic modifier that causes reproductive disorders. The consequences of TBT exposure on postejaculatory sperm remain unknown. The present study was aimed at identifying structural, genomic, and epigenomic consequences of TBT exposure to postejaculatory sperm. Bovine sperm were exposed to TBT (0, 1, 10, 100 nM) for 24 h followed by quantification of sperm kinematics, DNA integrity, and methylation status. No differences were detected in sperm kinematics or capacitation status. However, acrosome integrity was compromised at both 0 and 24 h (P ≤ 0.05). Sperm DNA integrity was also negatively affected after 24 h. Whole-genome methyl-seq revealed ~750 differentially methylated regions (DMRs) associated with exposure to TBT. Ingenuity Pathway Analyses and Gene Ontology identified embryo development, cell signaling, and transcriptional regulation as the most relevant bio-functions of TBT altered DMRs. In conclusion, postejaculatory mammalian sperm exposure to TBT negatively affected parameters important for sperm function while altering DNA integrity and the methylation profile of gene promoter regions. Consequences of sperm exposure to TBT included cellular and molecular mechanisms that are important for sperm function but remain undetected by routine clinical analyses. These findings provide new insight into environmental impacts on postejaculatory sperm structure and function.

Exposure to toxins causes lasting damaging effects on the body. Numerous studies in humans and animals suggest that diet has the potential to modify the epigenome and these modifications can be inherited transgenerationally, but few studies investigate how diet can protect against negative effects of toxins. Potential evidence in the primary literature supports that caloric restriction, high-fat diets, high protein-to-carbohydrate ratios, and dietary supplementation protect against environmental toxins and strengthen these effects on their offspring's epigenome. Most notably, the timing when dietary interventions are given - during a parent's early development, pregnancy, and/or lifetime - result in similar transgenerational epigenetic durations. This implies the existence of multiple opportunities to strategically fortify the epigenome. This narrative review explores how to best utilize dietary modifications to modify the epigenome to protect future generations against negative health effects of persistent environmental toxins. Furthermore, by suggesting an ideal diet with specific micronutrients, macronutrients, and food groups, epigenetics can play a key role in the field of preventive medicine. Based on these findings, longitudinal research should be conducted to determine if a high protein, high-fat, and low-carbohydrate diet during a mother's puberty or pregnancy can epigenetically protect against alcohol, tobacco smoke, and air pollution across multiple generations.

Histone H4K20 methylation is critical in regulating the cell cycle, DNA damage response, and gene repression in proliferating cells. However, its role in the heart remains poorly understood. Our previous work revealed that histone H4K20 tri-methylation is elevated in acute cell models of cardiomyocyte hypertrophy but is reduced in mouse models of cardiac hypertrophy and ischemia. Although these findings highlight the dynamic nature of this modification and its significance in regulating gene expression, the data on enzymes regulating H4K20 methylation is sparse. To build upon this work and investigate H4K20 di-methylation and the enzymes modulating this site in cardiac pathology, we quantified histone H4K20 di-methylation and 12 methyltransferases and demethylases across one cell model, two mouse models of cardiac dysfunction, and cardiac tissue from heart failure patients. While we observed no global changes in H4K20 di-methylation, we detected alterations in methyltransferases KMT5C and SMYD5 and demethylases RAD23A and KDM7C in humans and mice. These findings suggest changes in H4K20 di-methylation may occur on an individual gene basis but do not lead to global alterations in H4K20 di-methylation. Additionally, this work identified four enzymes differentially modulated in cardiac dysfunction to advance our understanding of epigenetic mechanisms involved in heart disease.

The Nile tilapia (Oreochromis niloticus) exhibits a strong metabolic response to dietary carbohydrates (CHO). Short-term refeeding after fasting with a high-carbohydrate (HC) diet has been shown to modulate CHO metabolism, but the role of epigenetic regulation in this response remains unclear. This study investigated how short-term refeeding with either a HC [639.2 g kg^-1 diet]/low-protein [164.9 g kg^-1 diet] (HC/LP) diet or a low-CHO [47.4 g kg^-1 diet]/high-protein [607.9 g kg^-1 diet] (LC/HP) diet influences global DNA methylation and demethylation, histone modifications, and mRNA levels of epigenetic regulators in the liver and muscle of juvenile and adult Nile tilapia. Following a 4-day fasting period, fish were refed for 4 days with either HC/LP or LC/HP diets. Compared to the fasted state, refeeding with either diet altered epigenetic markers by: (1) decreasing hepatic global DNA 5-mC oxidative derivatives-5-hmdC in juveniles, and both 5-hmdC and 5-cadC in adults; (2) inducing histone hypermethylation and/or hyperacetylation - H3K9ac (hepatic) and H3K36me3 (muscular) in juveniles, and H3K9me3 and H3K9ac (muscular) in adults; and (3) promoting expression of enzymes related to DNA hypermethylation (upregulated dnmt, downregulated tet) and histone hypermethylation/acetylation (upregulated setd1b, kmt2, suv39h1b; downregulated kdm4, sirt5). Diet-specific effects included hepatic H3K36 hypomethylation and H3K9 hypoacetylation in juveniles fed HC/LP, accompanied by upregulation of kdm4b, kdm4c, and sirt5. In adults, HC/LP refeeding induced muscular DNA hypomethylation and H3K9 hypoacetylation, associated with upregulation of tet, sirt2, and sirt5. Refeeding following fasting induced histone hypermethylation and/or hyperacetylation, while HC refeeding was particularly associated with muscular global DNA hypomethylation and histone hypoacetylation/methylation.

This study examines how the alcohol metabolite acetaldehyde modulates mRNA methylation and expression of ethanol-metabolizing genes, uncovering its epigenetic role in ethanol metabolism. Using neuron-like (SH-SY5Y) and non-neuronal (SW620) cellular models, we examined the effects of chronic intermittent acetaldehyde (CIA) exposure and subsequent withdrawal (CIA+WD) on global RNA m6A modifications and the methylation and expression of three brain ethanol-metabolizing genes: CAT (catalase), CYP2E1 (cytochrome P450 2E1), and ALDH2 (aldehyde dehydrogenase 2). A 3-week CIA exposure, with or without 24-hour withdrawal, did not significantly alter global m6A methylation levels in either cell line. However, acetaldehyde exposure/withdrawal induced hypermethylation at the mRNA stop codon regions of ALDH2 (CIA: p = 0.002; CIA+WD: p = 0.055) and CAT (CIA: p = 0.077; CIA+WD: p = 0.036) in SH-SY5Y cells, but not in SW620 cells. Furthermore, ALDH2 mRNA expression was significantly upregulated in both cell types following exposure (SH-SY5Y: p = 0.073 [CIA] and 0.00002 [CIA+WD]; SW620: p = 0.0009 [CIA] and 0.00008 [CIA+WD]). In contrast, CYP2E1 mRNA methylation and the expression of CYP2E1 and CAT remained unchanged. These findings highlight the cell-specific epigenetic effects of acetaldehyde, particularly its role in modulating mRNA methylation and expression of ALDH2, a key enzyme in alcohol metabolism.