Promoter DNA Methylation in GWAS-Identified Genes as Potential Functional Elements for Blood Pressure: An Observational and Mendelian Randomization Study

Genome-wide association studies have identified numerous genetic loci for blood pressure (BP). However, the relationships of functional elements inside these loci with BP are not fully understood. This study represented an effort to determine if promoter DNA methylations inside BP-associated loci were associated with BP.We conducted a cross-sectional study investigating the association between promoter DNA methylations of 10 candidate genes and BP in 1,241 Chinese individuals. Twenty-one genomic fragments in the CpG Islands were sequenced. The associations of methylation levels with BP and hypertension were assessed in regression models. Mendelian randomization (MR) analysis was then applied to find supporting evidence for the identified associations.A total of 413 DNA methylation sites were examined in an observational study. Methylation levels of 24 sites in PRDM6, IGFBP3, SYT7, PDE3A, TBX2 and C17orf82 were significantly associated with BP. Methylation levels of PRDM6 and SYT7 were significantly associated with hypertension. Methylation levels of five sites (including cg06713098) in IGFBP3 were significantly associated with DBP. MR analysis found associations between the methylation levels of six CpG sites (cg06713098, cg14228300, cg23193639, cg21268650, cg10677697 and cg04812164) around the IGFBP3 promoter and DBP. Methylation levels of cg14228300 and cg04812164 were associated with SBP. By further applying several MR methods we showed that the associations may not be due to pleiotropy. Association between IGFBP3 mRNA levels in blood cells and BP was also found in MR analysis. This study identified promoter methylation as potential functional element for BP. The identified methylations may be involved in the regulatory pathway linking genetic variants to BP.

Genetic and Epigenetic Targeting Therapy for Pediatric Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia is the most common malignancy in children and is characterized by numerous genetic and epigenetic abnormalities. Epigenetic mechanisms, including DNA methylations and histone modifications, result in the heritable silencing of genes without a change in their coding sequence. Emerging studies are increasing our understanding of the epigenetic role of leukemogenesis and have demonstrated the potential of DNA methylations and histone modifications as a biomarker for lineage and subtypes classification, predicting relapse, and disease progression in acute lymphoblastic leukemia. Epigenetic abnormalities are relatively reversible when treated with some small molecule-based agents compared to genetic alterations. In this review, we conclude the genetic and epigenetic characteristics in ALL and discuss the future role of DNA methylation and histone modifications in predicting relapse, finally focus on the individual and precision therapy targeting epigenetic alterations.

Genome-wide detection of cytosine methylations in plant from Nanopore data using deep learning

In plants, cytosine DNA methylations (5mCs) can happen in three sequence contexts as CpG, CHG, and CHH (where H = A, C, or T), which play different roles in the regulation of biological processes. Although long Nanopore reads are advantageous in the detection of 5mCs comparing to short-read bisulfite sequencing, existing methods can only detect 5mCs in the CpG context, which limits their application in plants. Here, we develop DeepSignal-plant, a deep learning tool to detect genome-wide 5mCs of all three contexts in plants from Nanopore reads. We sequence Arabidopsis thaliana and Oryza sativa using both Nanopore and bisulfite sequencing. We develop a denoising process for training models, which enables DeepSignal-plant to achieve high correlations with bisulfite sequencing for 5mC detection in all three contexts. Furthermore, DeepSignal-plant can profile more 5mC sites, which will help to provide a more complete understanding of epigenetic mechanisms of different biological processes.

DNA Methylation Is Correlated with Oxidative Stress in Myelodysplastic Syndrome—Relevance as Complementary Prognostic Biomarkers

Oxidative stress and abnormal DNA methylation have been implicated in cancer, including myelodysplastic syndromes (MDSs). This fact leads us to investigate whether oxidative stress is correlated with localized and global DNA methylations in the peripheral blood of MDS patients. Sixty-six MDS patients and 26 healthy individuals were analyzed. Several oxidative stress and macromolecule damage parameters were analyzed. Localized (gene promotor) and global DNA methylations (5-mC and 5-hmC levels; LINE-1 methylation) were assessed. MDS patients had lower levels of reduced glutathione and total antioxidant status (TAS) and higher levels of peroxides, nitric oxide, peroxides/TAS, and 8-hydroxy-2-deoxyguanosine compared with controls. These patients had higher 5-mC levels and lower 5-hmC/5-mC ratio and LINE-1 methylation and increased methylation frequency of at least one methylated gene. Peroxide levels and peroxide/TAS ratio were higher in patients with methylated genes than those without methylation and negatively correlated with LINE-1 methylation and positively with 5-mC levels. The 5-hmC/5-mC ratio was significantly associated with progression to acute leukemia and peroxide/TAS ratio with overall survival. This study points to a relationship between oxidative stress and DNA methylation, two common pathogenic mechanisms involved in MDS, and suggests the relevance of 5-hmC/5-mC and peroxide/TAS ratios as complementary prognostic biomarkers.

A comparative analysis of computational tools for the prediction of epigenetic DNA methylation from long-read sequencing data

Recent development of Oxford Nanopore long-read sequencing has opened new avenues of identifying epigenetic DNA methylation. Among the different epigenetic DNA methylations, N6-methyladenosine is the most prevalent DNA modification in prokaryotes and 5-methylcytosine is common in higher eukaryotes. Here we investigated if N6-methyladenosine and 5-methylcytosine modifications could be predicted from the nanopore sequencing data. Using publicly available genome sequencing data of Saccharomyces cerevisiae, we compared the open-access computational tools, including Tombo, mCaller, Nanopolish and DeepSignal for predicting 6mA and 5mC. Our results suggest that Tombo and mCaller can predict DNA N6-methyladenosine modifications at a specific location, whereas, Tombo dampened fraction, Nanopolish methylation likelihood and DeepSignal methylation probability have comparable efficiency for 5-methylcytosine prediction from Oxford Nanopore sequencing data.

Epigenome-wide association study on asthma and chronic obstructive pulmonary disease overlap reveals aberrant DNA methylations related to clinical phenotypes

We hypothesized that epigenetics is a link between smoking/allergen exposures and the development of Asthma and chronic obstructive pulmonary disease (ACO). A total of 75 of 228 COPD patients were identified as ACO, which was independently associated with increased exacerbations. Microarray analysis identified 404 differentially methylated loci (DML) in ACO patients, and 6575 DML in those with rapid lung function decline in a discovery cohort. In the validation cohort, ACO patients had hypermethylated PDE9A (+ 30,088)/ZNF323 (− 296), and hypomethylated SEPT8 (− 47) genes as compared with either pure COPD patients or healthy non-smokers. Hypermethylated TIGIT (− 173) gene and hypomethylated CYSLTR1 (+ 348)/CCDC88C (+ 125,722)/ADORA2B (+ 1339) were associated with severe airflow limitation, while hypomethylated IFRD1 (− 515) gene with frequent exacerbation in all the COPD patients. Hypermethylated ZNF323 (− 296) / MPV17L (+ 194) and hypomethylated PTPRN2 (+ 10,000) genes were associated with rapid lung function decline. In vitro cigarette smoke extract and ovalbumin concurrent exposure resulted in specific DNA methylation changes of the MPV17L / ZNF323 genes, while 5-aza-2′-deoxycytidine treatment reversed promoter hypermethylation-mediated MPV17L under-expression accompanied with reduced apoptosis and decreased generation of reactive oxygen species. Aberrant DNA methylations may constitute a determinant for ACO, and provide a biomarker of airflow limitation, exacerbation, and lung function decline.

Effect of ABCG1 gene DNA methylations on the lipid-lowering efficacy of simvastatin

Aim: We investigated the effect of ABCG1 gene DNA methylation in the lipid-lowering efficacy of simvastatin. Materials & methods: An extreme sampling approach was used to select 211 individuals from the top and bottom 15% of adjusted lipid-lowering response residuals to simvastatin after eight consecutive weeks. DNA methylation was measured before treatment by the MethylTarget bisulfite sequencing method. Results: ABCG1_A DNA methylations were negatively associated with baseline high-density lipoprotein cholesterol (HDL-C) and the change in HDL-C after treatment. ABCG1_C methylations were also related to the change in triglyceride and HDL-C. Moreover, mean ABCG1_A and ABCG1_C methylations explain 7.2% of the ΔTC (total cholesterol) and 17.5% of the ΔHDL-C level variability, respectively. Conclusion: DNA methylations at the ABCG1 gene play significant inhibitory effects in the lipid-lowering therapy of simvastatin.

Interplay between DNA and RNA Modifications: A Constantly Evolving Process

The epigenome refers to the entirety of DNA methylations, histone modifications, nucleosome occupancy, and coding and non-coding RNAs (and their modifications) in different cell types [...]