Epigenetics最新文献

Cattle skeletal muscle development is a complex and highly coordinated biological process mediated by a series of myogenic regulators, which plays a critical role in beef yield and quality. Long non-coding RNAs (lncRNAs) have been shown to regulate skeletal muscle development. However, the molecular mechanism by which lncRNAs regulate skeletal muscle development is largely unknown. We performed transcriptome analysis of muscle tissues of adult and embryo Angus cattle to investigate the mechanism by which lncRNA regulates skeletal muscle development between adult and embryo cattle. A total of 37,115 candidate lncRNAs were detected, and a total of 1,998 lncRNAs were differentially expressed between the muscle tissue libraries of adult and embryo cattle, including 1,229 up-regulated lncRNAs and 769 down-regulated lncRNAs (adult cattle were the control group). We verified the expression of 7 differentially expressed lncRNAs by quantitative real-time PCR (RT-qPCR), and analysed the tissue expression profile of lnc000100, which is down-regulated in the longest dorsal muscle during foetal life and which is highly specifically expressed in muscle tissue. We found that the interference of lnc000100 significantly inhibited cell proliferation and promoted cell differentiation. Lnc000100 was located in the nucleus by RNA-FISH. Our research provides certain resources for the analysis of lncRNA regulating cattle skeletal muscle development, and may also provide new insights for improving beef production and breed selection.

DNA methylation (DNAm) epigenome-wide association studies (EWAS) have been performed on diverse ethnicities to discover novel biomarkers associated with various diseases, such as cancers, autoimmune diseases, and neurological disorders. However, genetic polymorphisms can influence DNAm levels resulting in methylation quantitative trait loci (meQTL). These can be either direct effects, by altering the sequence of the methylation (CpG) site itself, or, in the case of array-based measures, indirectly altering the detection probe-binding site interaction. Given that genetic variant frequencies associated with meQTL can differ between population groups, these have the potential to confound EWAS observations, particularly in multi-ethnic populations. In this study, we analysed publicly available DNA methylation profiles (450K array), consisting of 1342 individuals from 6 distinct ancestral groups. We investigate two distinct tools (GapHunter and MethylToSNP) specifically designed to identify CpG sites that may be influenced by genetic variation. Results from this aggregated trans-ancestral epigenome-wide dataset suggest that both tools fail to consistently identify not only rarer (MAF < 0.05) genetic variant effects but also more than half of sites predicted to be associated with variants with much higher allele frequencies (MAF >0.2). In addition, there is a relatively low concordance in the detection of polymorphic CpGs between GapHunter and MethylToSNP. Screening of CpG site associations from EWAS using either of these tools is unlikely to be a robust or comprehensive means of identifying all genetic variant confounding effects.

Background: Dietary intake of antioxidants such as vitamins C and E protect against oxidative stress, and may also be associated with altered DNA methylation patterns.

Methods: We meta-analysed epigenome-wide association study (EWAS) results from 11,866 participants across eight population-based cohorts to evaluate the association between self-reported dietary and supplemental intake of vitamins C and E with DNA methylation. EWAS were adjusted for age, sex, BMI, caloric intake, blood cell type proportion, smoking status, alcohol consumption, and technical covariates. Significant results of the meta-analysis were subsequently evaluated in gene set enrichment analysis (GSEA) and expression quantitative trait methylation (eQTM) analysis.

Results: In meta-analysis, methylation at 4,656 CpG sites was significantly associated with vitamin C intake at FDR ≤ 0.05. The most significant CpG sites associated with vitamin C (at FDR ≤ 0.01) were enriched for pathways associated with systems development and cell signalling in GSEA, and were associated with downstream expression of genes enriched in the immune response in eQTM analysis. Furthermore, methylation at 160 CpG sites was significantly associated with vitamin E intake at FDR ≤ 0.05, but GSEA and eQTM analysis of the top most significant CpG sites associated with vitamin E did not identify significant enrichment of any biological pathways investigated.

Conclusions: We identified significant associations of many CpG sites with vitamin C and E intake, and our results suggest that vitamin C intake may be associated with systems development and the immune response.

The prevalence and severity of many diseases differs by sex, potentially due to sex-specific patterns in DNA methylation. Autosomal sex-specific differences in DNA methylation have been observed in cord blood and placental tissue but are not well studied in saliva or in diverse populations. We sought to characterize sex-specific DNA methylation on autosomal chromosomes in saliva samples from children in the Future of Families and Child Wellbeing Study, a multi-ethnic prospective birth cohort containing an oversampling of Black, Hispanic and low-income families. DNA methylation from saliva samples was analysed on 796 children (50.6% male) at both ages 9 and 15 with DNA methylation measured using the Illumina HumanMethylation 450k array. An epigenome-wide association analysis of the age 9 samples identified 8,430 sex-differentiated autosomal DNA methylation sites (P < 2.4 × 10^-7), of which 76.2% had higher DNA methylation in female children. The strongest sex-difference was in the cg26921482 probe, in the AMDHD2 gene, with 30.6% higher DNA methylation in female compared to male children (P < 1 × 10^-300). Treating the age 15 samples as an internal replication set, we observed highly consistent results between the ages 9 and 15 measurements, indicating stable and replicable sex-differentiation. Further, we directly compared our results to previously published DNA methylation sex differences in both cord blood and saliva and again found strong consistency. Our findings support widespread and robust sex-differential DNA methylation across age, human tissues, and populations. These findings help inform our understanding of potential biological processes contributing to sex differences in human physiology and disease.

Asparaginase is an important agent for the treatment of acute lymphoblastic leukaemia (ALL), but it is occasionally associated with severe adverse events. Thus, for safer and more efficacious therapy, a clinical biomarker predicting asparaginase sensitivity is highly anticipated. Asparaginase depletes serum asparagine by deaminating asparagine into aspartic acid, and ALL cells are thought to be sensitive to asparaginase due to reduced asparagine synthetase (ASNS) activity. We have recently shown that allele-specific methylation of the ASNS gene is highly involved in asparaginase sensitivity in B-precursor ALL (BCP-ALL) by using next-generation sequence (NGS) analysis of bisulphite PCR products of the genomic DNA. Here, we sought to confirm the utility of methylation status of the ASNS gene evaluated with high-performance liquid chromatography (HPLC) analysis of bisulphite PCR products for future clinical applications. In the global methylation status of 23 CpG sites at the boundary region of promoter and exon 1 of the ASNS gene, a strong positive correlation was confirmed between the mean percent methylation evaluated with the HPLC method and that with the NGS method in 79 BCP-ALL cell lines (R² = 0.85, p = 1.3 × 10^-33) and in 63 BCP-ALL clinical samples (R² = 0.84, p = 5.0 × 10^-26). Moreover, methylation status of the ASNS gene evaluated with the HPLC method was significantly associated with in vitro asparaginase sensitivities as well as gene and protein expression levels of ASNS. These observations indicated that the ASNS gene methylation status evaluated with the HPLC method is a reliable biomarker for predicting the asparaginase sensitivity of BCP-ALL.

Phenotypic plasticity of metabolism and growth are essential for adaptation to new environmental conditions, such as those experienced during domestication. Epigenetic regulation plays a key role in this process but the underlying mechanisms are poorly understood, especially in the case of hydroxymethylation. Using reduced representation 5-hydroxymethylcytosine profiling, we compared the liver hydroxymethylomes in full-sib Nile tilapia with distinct growth rates (3.8-fold difference) and demonstrated that DNA hydroxymethylation is strongly associated with phenotypic divergence of somatic growth during the early stages of domestication. The 2677 differentially hydroxymethylated cytosines between fast- and slow-growing fish were enriched within gene bodies (79%), indicating a pertinent role in transcriptional regulation. Moreover, they were found in genes involved in biological processes related to skeletal system and muscle structure development, and there was a positive association between somatic growth and 5hmC levels in genes coding for growth factors, kinases and receptors linked to myogenesis. Single nucleotide polymorphism analysis revealed no genetic differentiation between fast- and slow-growing fish. In addition to unveiling a new link between DNA hydroxymethylation and epigenetic regulation of growth in fish during the initial stages of domestication, this study suggests that epimarkers may be applied in selective breeding programmes for superior phenotypes.

Prenatal maternal stress has a negative impact on child health but the mechanisms through which maternal stress affects child health are unclear. Epigenetic variation, such as DNA methylation, is a likely mechanistic candidate as DNA methylation is sensitive to environmental insults and can regulate long-term changes in gene expression. We recruited 155 mother-newborn dyads in the Democratic Republic of Congo to investigate the effects of maternal stress on DNA methylation in mothers and newborns. We used four measures of maternal stress to capture a range of stressful experiences: general trauma, sexual trauma, war trauma, and chronic stress. We identified differentially methylated positions (DMPs) associated with general trauma, sexual trauma, and war trauma in both mothers and newborns. No DMPs were associated with chronic stress. Sexual trauma was positively associated with epigenetic age acceleration across several epigenetic clocks in mothers. General trauma and war trauma were positively associated with newborn epigenetic age acceleration using the extrinsic epigenetic age clock. We tested the top DMPs for enrichment of DNase I hypersensitive sites (DHS) and found no enrichment in mothers. In newborns, top DMPs associated with war trauma were enriched for DHS in embryonic and foetal cell types. Finally, one of the top DMPs associated with war trauma in newborns also predicted birthweight, completing the cycle from maternal stress to DNA methylation to newborn health outcome. Our results indicate that maternal stress is associated with site-specific changes in DNAm and epigenetic age acceleration in both mothers and newborns.

Mastitis is among the main reasons women cease breastfeeding, which leads to them supplementing breast milk with artificial formula. In farm animals, mastitis results in significant economic losses and the premature culling of some animals. Nevertheless, researchers do not know enough about the effect of inflammation on the mammary gland. This article discusses the changes to DNA methylation in mouse mammary tissue caused by lipopolysaccharide-induced inflammation (4 h post-injection of lipopolysaccharide). We analysed the expression of some genes related to mammary gland function, epigenetic regulation, and the immune response. The analysis focused on three comparisons: inflammation during the first lactation, inflammation during second lactation with no history of inflammation, and inflammation during second lactation with previous inflammation. We identified differentially methylated cytosines (DMCs), differentially methylated regions (DMRs), and some differentially expressed genes (DEGs) for each comparison. The three comparisons shared some DEGs; however, few DMCs and only one DMR were shared. These observations suggest that inflammation is one of several factors affecting epigenetic regulation during successive lactations. Furthermore, the comparison between animals in second lactation with and without inflammation, with no inflammation history during first lactation showed a different pattern compared to the other conditions in this experiment. This indicates that inflammation history plays an important role in determining epigenetic changes. The data presented in this study suggest that lactation rank and previous inflammation history are equally important when explaining mammary tissue gene expression and DNA methylation changes.Abbreviations: RRBS, reduced representation bisulfite sequencing; RT-qPCR, real-time quantitative polymerase chain reaction; MEC, mammary epithelial cells; TSS, transcription start site; TTS, transcription termination site; UTR, untranslated region; SINE, short interspersed nuclear element; LINE, long interspersed nuclear element; CGI, CpG island; DEG, differentially expressed gene; DMC, differentially methylated cytosine; DMR, differentially methylated region; GO term, gene ontology term; MF, molecular function; BP, biological process.

Co-occurrence of injection drug use (IDU) and hepatitis C virus infection (HCV) is common in people living with HIV (PLWH) and leads to significantly increased mortality. Epigenetic clocks derived from DNA methylation (DNAm) are associated with disease progression and all-cause mortality. In this study, we hypothesized that epigenetic age mediates the relationships between the co-occurrence of IDU and HCV with mortality risk among PLWH. We tested this hypothesis in the Veterans Aging Cohort Study (n = 927) by using four established epigenetic clocks of DNAm age (i.e., Horvath, Hannum, Pheno, Grim). Compared to individuals without IDU and HCV (IDU-HCV-), participants with IDU and HCV (IDU+HCV+) showed a 2.23-fold greater risk of mortality estimated using a Cox proportional hazards model (hazard ratio: 2.23; 95% confidence interval: 1.62-3.09; p = 1.09E-06). IDU+HCV+ was associated with a significantly increased epigenetic age acceleration (EAA) measured by 3 out of 4 epigenetic clocks, adjusting for demographic and clinical variables (Hannum: p = 8.90E-04, Pheno: p = 2.34E-03, Grim: p = 3.33E-11). Furthermore, we found that epigenetic age partially mediated the relationship between IDU+HCV+ and all-cause mortality, up to a 13.67% mediation proportion. Our results suggest that comorbid IDU with HCV increases EAA in PLWH that partially mediates the increased mortality risk.

Alternative splicing is a process causing mRNA translation to produce different proteins, and it is crucial for the development of tumours. In this study, we constructed a prognostic model related to alternative splicing events in hepatocarcinoma using bioinformatics analysis, including the alternative splicing of CSAD, AFMID, ZDHHC16, and IRF3. The model is an independent prognostic factor and can accurately predict a patient's prognosis. IRF3 is a transcription factor related to the immune response. Its alternative splicing can affect the expression of various genes related to prognosis and plays an essential role in the tumour microenvironment. We also verified the expression of IRF3 exon skipping isoform in hepatocarcinoma at the mRNA level. In conclusion, we discovered that the alternative splicing of IRF3 is essential for the development of hepatocarcinoma. This study provides new insight into the development of treatments for hepatocarcinoma.