Deoxyribonucleic Acid Methylation Research Articles

Epigenetic changes caused by diabetes and their potential role in the development of periodontitis.

Aims/IntroductionPeriodontal disease, a chronic inflammation induced by bacteria, is closely linked with diabetes mellitus. Many complications associated with diabetes are related to epigenetic changes. However, the exact epigenetic changes whereby diabetes affects periodontal disease remain largely unknown. Thus, we sought to investigate the role of diabetes‐dependent epigenetic changes of gingival tissue in the susceptibility to periodontal disease.Materials and MethodsWe studied the effect of streptozotocin‐induced diabetes in minipigs on gingival morphological and epigenetic tissue changes. Accordingly, we randomly divided six minipigs into two groups: streptozotocin‐induced diabetes group, n = 3; and non‐diabetes healthy control group, n = 3. After 85 days, all animals were killed, and gingival tissue was collected for histology, deoxyribonucleic acid methylation analysis and immunohistochemistry.ResultsA diabetes mellitus model was successfully created, as evidenced by significantly increased blood glucose levels, reduction of pancreatic insulin‐producing β‐cells and histopathological changes in the kidneys. The gingival tissues in the diabetes group presented acanthosis of both gingival squamous epithelium and sulcular/junctional epithelium, and a significant reduction in the number and length of rete pegs. Deoxyribonucleic acid methylation analysis showed a total of 1,163 affected genes, of which 599 and 564 were significantly hypermethylated and hypomethylated, respectively. Immunohistochemistry staining showed that the hypomethylated genes – tumor necrosis factor‐α and interleukin‐6 – were positively expressed under the junctional epithelium area in the diabetes group.ConclusionsDiabetes mellitus induces morphological and epigenetic changes in periodontal tissue, which might contribute to the increased susceptibility of periodontal diseases in patients with diabetes.

XXYLT1 methylation contributes to the occurrence of lung adenocarcinoma: Methylation and lung adenocarcinoma.

Background:There is evidence that DNA methylation play major roles in lung cancer. In our previously study, C3 or f21 , also referred to as XXYLT1, rs2131877 polymorphism is associated with a reduced risk of lung adenocarcinoma. So, we explored the role of XXYLT1 methylation in lung adenocarcinoma.Methods:This study was conducted in 2 steps. In the first step, we recruited 15 patients with lung adenocarcinoma. Cancer tissues and para-carcinoma tissues were obtained from each of the patients. In the second step, 150 patients with lung adenocarcinom were enrolled, and cancer and normal lung tissue were obtained from each patients, respectively. The expression levels of XXYLT1 mRNA were determined, the deoxyribonucleic acid methylation status was analyzed by MassARRAY Spectrometry. The methylation data of individual units were generated by EpiTyper v1.0.5 software.Results:The XXYLT1 mRNA expression was significantly lower in cancer tissues than in para-carcinoma and normal lung tissues. Meanwhile, the methylation rates of three CpG units (CpG_23, CpG_25, and CpG_60.61.62.63.64.65) within the XXYLT1 gene were higher in cancer tissues compared to the para-carcinoma and the normal lung tissues. This difference was particularly significant in male patients.Conclusions:Our results suggested that methylation of XXYLT1 may have significance in the pathogenesis of lung adenocarcinoma.

Fetal gastroschisis: Maternal and fetal methylation profile.

The purpose of this study was to describe the genomic deoxyribonucleic acid (DNA) methylation profile in fetuses with gastroschisis, determine whether the profile was inherited, and investigate any possible correlations with maternal risk factors. Genome-wide DNA methylation analysis of 96 blood samples was performed using the Illumina Human Methylation 850K BeadChip. The blood samples were collected as follows: 32 from the umbilical cord of fetuses with gastroschisis, 32 from their respective mothers, 16 from the umbilical cord of fetuses without malformation, and 16 from their respective mothers. The differential DNA methylation analysis showed a significant difference between the groups. The enrichment analysis resulted in 12 sites related to T-cell activation (p=0.0128). The sites with different methylation status contained 10 genes, three of which were related to the beta-2-microglobulin gene. The methylation profile observed in the fetuses with gastroschisis was not inherited from the mothers. In addition, there was no association between maternal urinary tract infection, smoking, and alcohol use and different methylated sites. We established the methylation profile of gastroschisis fetuses, which differs from that of normal fetuses. The profile was not inherited and did not correlate with maternal risk factors.

DNA Methylation at Birth is Associated with Childhood Serum Immunoglobulin E Levels.

Immunoglobulin E (IgE) is known to play an important role in allergic diseases. Epigenetic traits acquired due to modification of deoxyribonucleic acid (DNA) methylation (DNAm) in early life may have phenotypic consequences through their role in transcriptional regulation with relevance to the developmental origins of diseases including allergy. However, epigenome-scale studies on the longitudinal association of cord blood DNAm with IgE over time are lacking. Our study aimed to examine the association of DNAm at birth with childhood serum IgE levels during early life. Genome-scale DNAm and total serum IgE measured at birth, 5, 8, and 11 years of children in the Taiwan Maternal and Infant Cohort Study were included in the study in the discovery stage. Linear mixed models were implemented to assess the association between cord blood DNAm at ~310K 5′-cytosine-phosphate-guanine-3′ (CpG) sites with repeated IgE measurements, adjusting for cord blood IgE. Identified statistically significant CpGs (at a false discovery rate, FDR, of 0.05) were further tested in an independent replication cohort, the Isle of Wight (IoW) birth cohort. We mapped replicated CpGs to genes and conducted gene ontology analysis using ToppFun to identify significantly enriched pathways and biological processes of the genes. Cord blood DNAm of 273 CpG sites were significantly (FDR = 0.05) associated with IgE levels longitudinally. Among the identified CpGs available in both cohorts (184 CpGs), 92 CpGs (50%) were replicated in the IoW in terms of consistency in direction of associations between DNA methylation and IgE levels later in life, and 16 of the 92 CpGs showed statistically significant associations (P < .05). Gene ontology analysis identified 4 pathways (FDR = 0.05). The identified 16 CpG sites had the potential to serve as epigenetic markers associated with later IgE production, beneficial to allergic disease prevention and intervention.

A New Optimized Wrapper Gene Selection Method for Breast Cancer Prediction

Machine-learning algorithms have been widely used in breast cancer diagnosis to help pathologists and physicians in the decision-making process. However, the high dimensionality of genetic data makes the classification process a challenging task. In this paper, we propose a new optimized wrapper gene selection method that is based on a nature-inspired algorithm (simulated annealing (SA)), which will help select the most informative genes for breast cancer prediction. These optimal genes will then be used to train the classifier to improve its accuracy and efficiency. Three supervised machine-learning algorithms, namely, the support vector machine, the decision tree, and the random forest were used to create the classifier models that will help to predict breast cancer. Two different experiments were conducted using three datasets: Gene expression (GE), deoxyribonucleic acid (DNA) methylation, and a combination of the two. Six measures were used to evaluate the performance of the proposed algorithm, which include the following: Accuracy, precision, recall, specificity, area under the curve (AUC), and execution time. The effectiveness of the proposed classifiers was evaluated through comprehensive experiments. The results demonstrated that our approach outperformed the conventional classifiers as expected in terms of accuracy and execution time. High accuracy values of 99.77%, 99.45%, and 99.45% have been achieved by SA-SVM for GE, DNA methylation, and the combined datasets, respectively. The execution time of the proposed approach was significantly reduced, in comparison to that of the traditional classifiers and the best execution time has been reached by SA-SVM, which was 0.02, 0.03, and 0.02 on GE, DNA methylation, and the combined datasets respectively. In regard to precision and specificity, SA-RF obtained the best result of 100 on GE dataset. While SA-SVM attained the best recall result of 100 on GE dataset.

Altered Deoxyribonucleic Acid Methylation Underlies the Aberrant Expression of Androgen Synthesis Related Genes in Polycystic Ovary Syndrome

To determine the correlation between deoxyribonucleic acid methylation and gene expression of cytochrome P450 family 19 subfamily A polypeptide 1 cytochrome P450 family 19 subfamily a member 1, anti-Mullerian hormone and anti-Mullerian hormone receptor type 2, which regulate follicle development and androgen metabolism in polycystic ovary syndrome pathogenesis. The levels of cytochrome P450 family 19 subfamily a member 1, anti-Mullerian hormone and anti-Mullerian hormone receptor type 2 messenger ribonucleic acid and protein expression were evaluated by various techniques in polycystic ovary syndrome patients. Estradiol, androstenedione and anti-Mullerian hormone levels were also tested in follicular fluid. In order to quantify the connection between deoxyribonucleic acid methylation and gene expression, we conducted Pearson product-moment correlation coefficient analyses. The estradiol level did not alter, however the androstenedione level was increased. Polycystic ovary syndrome granulosa cells were hypermethylated cytochrome P450 family 19 subfamily a member 1, but hypomethylated anti- Mullerian hormone and anti-Mullerian hormone receptor type 2. In general, the greater the amount of deoxyribonucleic acid methylation, the lower the level of downstream messenger ribonucleic acid and protein expression. Aromatase enzyme activity is regulated by deoxyribonucleic acid methylation and a hormone called follicular estradiol/androstenedione ratio is linked with it. A prior study reported that anti- Mullerian hormone inhibits aromatase in granulosa cells and therefore the inverse connection between cytochrome P450 family 19 subfamily a member 1 and anti-Mullerian hormone confirms that finding. Our study suggests alterations in deoxyribonucleic acid methylation as the underlying mechanism of aberrant gene expression of cytochrome P450 family 19 subfamily a member 1, anti-Mullerian hormone and anti- Mullerian hormone receptor type 2 and polycystic ovary syndrome pathogenesis.

Enhanced neoplasia detection in chronic ulcerative colitis: the ENDCaP-C diagnostic accuracy study

Background Chronic ulcerative colitis is a large bowel inflammatory condition associated with increased colorectal cancer risk over time, resulting in 1000 colectomies per year in the UK. Despite intensive colonoscopic surveillance, 50% of cases progress to invasive cancer before detection. Detecting early (precancer) molecular changes by analysing biopsies from routine colonoscopy should increase neoplasia detection. Objectives To establish a deoxyribonucleic acid (DNA) marker panel associated with early neoplastic changes in ulcerative colitis patients. To develop the DNA methylation test for high-throughput analysis within the NHS. To prospectively evaluate the test within the existing colonoscopy surveillance programme. Design Module 1 analysed 569 stored biopsies from neoplastic and non-neoplastic sites/patients using pyrosequencing for 11 genes that were previously reported to have altered promoter methylation associated with colitis-associated neoplasia. Classifiers were constructed to predict neoplasia based on gene combinations. Module 2 translated analysis to a NHS laboratory, assessing next-generation sequencing to increase speed and reduce cost. Module 3 applied the molecular classifiers within a prospective diagnostic accuracy study, in the existing ulcerative colitis surveillance programme. Comparisons were made between baseline and reference colonoscopies undertaken in a stratified patient sample 6–12 months later. Setting Thirty-one UK hospitals. Participants Patients with chronic ulcerative colitis, either for at least 10 years and extensive disease, or with primary sclerosing cholangitis. Interventions An optimised DNA methylation classifier tested on routine mucosal biopsies taken during colonoscopy. Main outcome Identifying ulcerative colitis patients with neoplasia. Results Module 1 selected five genes with specificity for neoplasia. The optimism-adjusted area under the receiver operating characteristic curve for neoplasia was 0.83 (95% confidence interval 0.79 to 0.88). Precancerous neoplasia showed a higher area under the receiver operating characteristic curve of 0.88 (95% confidence interval 0.84 to 0.92). Background mucosa had poorer discrimination (optimism-adjusted area under the receiver operating characteristic curve was 0.68, 95% confidence interval 0.62 to 0.73). Module 2 was unable to develop a robust next-generation sequencing assay because of the low amplification rates across all genes. In module 3, 818 patients underwent a baseline colonoscopy. The methylation assay (testing non-neoplastic mucosa) was compared with pathology assessments for neoplasia and showed a diagnostic odds ratio of 2.37 (95% confidence interval 1.46 to 3.82; p = 0.0002). The probability of dysplasia increased from 11.1% before testing to 17.7% after testing (95% confidence interval 13.0% to 23.2%), with a positive methylation result suggesting added value in neoplasia detection. To determine added value above colonoscopy alone, a second (reference) colonoscopy was performed in 193 patients without neoplasia. Although the test showed an increased number of patients with neoplasia associated with primary methylation changes, this failed to reach statistical significance (diagnostic odds ratio 3.93; 95% confidence interval 0.82 to 24.75; p = 0.09). Limitations Since the inception of ENDCaP-C, technology has advanced to allow whole-genome or methylome testing to be performed. Conclusions Methylation testing for chronic ulcerative colitis patients cannot be recommended based on this study. However, following up this cohort will reveal further neoplastic changes, indicating whether or not this test may be identifying a population at risk of future neoplasia and informing future surveillance programmes. Trial registration Current Controlled Trials ISRCTN81826545. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership, and will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 1. See the NIHR Journals Library website for further project information.

Effect of vitamin D3 supplementation upon the metabolic and DNA methylation profile of cystic fibrosis patients

Background: Cystic fibrosis (CF) is a genetic disease that affects the transmembrane conductance regulator gene responsible for modulating chloride ion transportation in the cell membrane. Hypovitaminosis D is frequently observed among fibrocystic disease patients. Therefore, this study was aimed to evaluate the effect of vitamin D3 supplementation in patients with CF concerning their metabolic and deoxyribonucleic acid (DNA) methylation profiles. Methodology: A clinical trial involving 12 CF patients was carried out in Joao Pessoa. After assessment of hypovitaminosis D prevalence in the studied population, four patients with vitamin D3 insufficiency/deficiency were administered cholecalciferol megadose supplementation in addition to biochemical examinations and analysis of inflammatory and epigenetic indicators. The DNA methylation profile of the studied genes' promoter regions was determined through a qualitative methylation restriction enzyme technique. Data were analyzed using the Statistical Package for the Social Sciences 25.0 software for T-tests, Mann-Whitney, and Wilcoxon test calculations. Results: Hypovitaminosis D was observed in 58%, 33% of the studied individuals. Patients with hypovitaminosis D reported blood sugar, glutamic-pyruvic transaminase (ALT), and uric acid levels significantly higher (p = 0.02; p = 0.05; p = 0.02, respectively) compared to individuals with sufficient 25-hydroxyvitamin D (25(OH)D), as well as elevated inflammatory values. Supplementation did not influence epigenetic nor metabolic parameters significantly, although the mean 25(OH)D serum concentration value increased from 18.3 ng/dl to 34.1 ng/dl (p = 0.06). Conclusion: Cholecalciferol megadose elevated 25(OH)D serum levels, although it did not alter inflammatory, glycemic, or epigenetic parameters. This encourages future studies on the matter since significant differences were found in blood sugar, uric acid, and ALT serum levels for the vitamin D3 insufficiency/deficiency group despite this study�s small sample size.

Mechanisms of DNA Abnormal Methylation in the Development of Lung Cancer in Rats

In order to study the mechanism of abnormal deoxyribonucleic acid methylation in the process of lung cancer in rats, Wistar rats are used as the research object. The lung cancer model of rats is established by bronchial perfusion of carcinogens. Hematoxylin-eosin staining is used to observe the pathological changes of lung tissue in rats. The overall methylation level of genome is analyzed by immunohistochemistry, and the methylation status is detected by methylation specific polymerase chain reaction. The results show that the nuclei of normal bronchial epithelial cells are brown and yellow uder optical microscope. With the development of carcinogenesis, the staining gradually fades to light yellow in the infiltrating nuclei of cancer cells. Compared with normal bronchial epithelial cells, the optical density and integrated optical density values of 5-mC immunohistochemistry decrease. The methylation frequency of p16 gene in atypical hyperplasia, carcinoma in situ and invasive cancer tissues is significantly higher than that in normal and proliferative tissues. The methylation frequency of p57 gene is significantly higher in carcinoma in situ and invasive tissues than in normal and proliferative tissues. Abnormal methylation-mediated down-regulation of p16 and p57 gene transcription may be an important molecular biological event in carcinogenesis of lung cancer rats induced by carcinogens. There are still some shortcomings in the research process, but the results of the study still provide some reference and guidance for exploring more precise mechanism in the future. Therefore, this study is a significant research topic.

Deoxyribonucleic acid methylation in the enhancer region of the CDKN2A/2B and CDKN2B-AS1 genes in blood vessels and cells in patients with carotid atherosclerosis

Aim. Comparative analysis of the deoxyribonucleic acid (DNA) methylation level in the enhancer region of the CDKN2A/2B and CDKN2B-AS1 genes (9p21.3 locus) in vessels with/without atherosclerotic lesions, as well as in leukocytes of patients with clinically relevant carotid artery (CA) atherosclerosis and healthy individuals.Material and methods. The group of patients with clinically relevant atherosclerosis included 22 individuals with severe stenosis (&gt;80%) of CA. Samples of atherosclerotic plaques, presenting CA regions, and great saphenous veins, as well as peripheral blood samples (leukocytes) were obtained from patients. The control group consisted of 14 individuals with the mild CA stenosis (£24%) and without hemodynamically relevant changes; peripheral blood samples were obtained from each of them. DNA methylation level was assessed by targeted bisulfite sequencing of amplicons.Results. The tissue-specific methylation of 31 CpG-site in the CDKN2A/2B and CDKN2B-AS1 gene enhancer was established: the vascular tissues significantly differed from the peripheral blood leukocytes. At the same time, there was an increase in the methylation level of both certain CpG sites and whole analyzed CA region affected by atherosclerosis (48,6 [34,8; 62,0]%), compared with intact vessels, both arteries (25,2 [23,1; 41,60]%, p=0,0001) and veins (35,0 [31,6; 40,0]%, p=0,0039). Patients had lower methylation levels in all CpG sites in blood leukocytes compared to blood vessel samples (8,7 [6,1; 9,7]%; p&lt;0,05). At the same time, the level of DNA methylation in the blood leukocytes of atherosclerotic patients does not differ from that in healthy individuals (9,3 [8,3; 13,6]%; p&gt;0,8).Conclusion. In the present study, the relationship between an increase in the DNA methylation in the enhancer of the CDKN2A/2B and CDKN2B-AS1 genes in CA and their atherosclerotic lesions was revealed, as well as the tissue-specific DNA methylation between vessels and peripheral blood leukocytes.

Signature based on molecular subtypes of deoxyribonucleic acid methylation predicts overall survival in gastric cancer.

BACKGROUNDGastric cancer (GC) ranks as the third leading cause of cancer-related death worldwide. Epigenetic alterations contribute to tumor heterogeneity in early stages.AIMTo identify the specific deoxyribonucleic acid (DNA) methylation sites that influence the prognosis of GC patients and explore the prognostic value of a model based on subtypes of DNA methylation.METHODSPatients were randomly classified into training and test sets. Prognostic DNA methylation sites were identified by integrating DNA methylation profiles and clinical data from The Cancer Genome Atlas GC cohort. In the training set, unsupervised consensus clustering was performed to identify distinct subgroups based on methylation status. A risk score model was built based on Kaplan-Meier, least absolute shrinkage and selector operation, and multivariate Cox regression analyses. A test set was used to validate this model.RESULTSThree subgroups based on DNA methylation profiles in the training set were identified using 1061 methylation sites that were significantly associated with survival. These methylation subtypes reflected differences in T, N, and M category, age, stage, and prognosis. Forty-one methylation sites were screened as specific hyper- or hypomethylation sites for each specific subgroup. Enrichment analysis revealed that they were mainly involved in pathways related to carcinogenesis, tumor growth, and progression. Finally, two methylation sites were chosen to generate a prognostic model. The high-risk group showed a markedly poor prognosis compared to the low-risk group in both the training [hazard ratio (HR) = 2.24, 95% confidence interval (CI): 1.28-3.92, P < 0.001] and test (HR = 2.12, 95%CI: 1.19-3.78, P = 0.002) datasets.CONCLUSIONDNA methylation-based classification reflects the epigenetic heterogeneity of GC and may contribute to predicting prognosis and offer novel insights for individualized treatment of patients with GC.

Placental maternally expressed gene3 differentially methylated region methylation profile is associated with maternal glucose concentration and newborn birthweight.

Aims/IntroductionEmerging evidence shows that epigenetic modifications occurring during fetal development in response to intrauterine exposures could be one of the mechanisms involved in the early determinants of adult metabolic disorders. This study aimed to investigate whether the placental maternally expressed gene 3 (MEG3) deoxyribonucleic acid (DNA) methylation profile is associated with maternal gestational diabetes mellitus status and newborn birthweight.Materials and MethodsSamples for measurement were collected from 23 women with gestational diabetes mellitus and 23 healthy controls. MEG3 gene expression and DNA methylation levels were assessed using quantitative real‐time polymerase chain reaction and MethylTargetTM, respectively. Pearson correlation analyses were used to examine associations between placental DNA methylation levels and clinical variables of interest. The associated results were adjusted by multivariate linear regression for maternal age, body mass index, height, gestational age and newborn sex as confounders.ResultsWe found that the DNA methylation levels in the MEG3 differentially methylated region were significantly different between the gestational diabetes mellitus and control groups on the maternal side of the placenta (40.64 ± 2.15 vs 38.33 ± 2.92; P = 0.004). Furthermore, the mean MEG3 DNA methylation levels were correlated positively with maternal fasting glucose concentrations (R = 0.603, P < 0.001) and newborn birthweight (R = 0.568, P < 0.001).ConclusionsThe placental DNA methylation status in the MEG3 differentially methylated region was correlated with maternal glucose concentrations and newborn birthweight. These epigenetic adaptations might contribute to late‐onset obesity, underlining the adverse intrauterine environment.

Epigenetic modifications in prostate cancer.

Prostate cancer is a major cause of cancer-related deaths among men worldwide. In addition to genomic alterations, epigenetic alterations accumulated in prostate cancer have been elucidated. While aberrant deoxyribonucleic acid hypermethylation in promoter CpG islands inactivates crucial genes associated with deoxyribonucleic acid repair, cell cycle, apoptosis or cell adhesion, aberrant deoxyribonucleic acid hypomethylation can lead to oncogene activation. Acetylation of histone is also deregulated in prostate cancer, which could cause aberrant super-enhancer formation and activation of genes associated with cancer development. Deregulations of histone methylation, such as an increase of trimethylation at position 27 of histone H3 by enhancer of zeste homolog2 overexpression, or other modifications, such as phosphorylation and ubiquitination, are also involved in prostate cancer development, and inhibitors targeting these epigenomic aberrations might be novel therapeutic strategies. In this review, we provide an overview of epigenetic alterations in the development and progression of prostate cancer, focusing on deoxyribonucleic acid methylation and histone modifications.

Theory, hormones and life history stages: an introduction to the symposium epigenetic variation in endocrine systems.

All organisms must respond to environmental stimuli, and most metazoans do so through endocrine system regulation. Hormonal fluctuations allow organisms to maintain and return to homeostasis following perturbations, making them vital for survival and fitness. Many components of the endocrine system (e.g., proteins, steroids, receptors, genome response elements, etc.) and the physiological and behavioral processes they regulate are conserved among vertebrates (e.g., the glucocorticoid stress response). However, there are sometimes dramatic differences among and within species, particularly in how hormonal variation affects phenotypes. Some such variation is driven by internal factors such as genetics, developmental stage, sex, individual age, and body condition in addition to external factors such as the type, magnitude, and duration of environmental stimuli. Eco-evolutionary endocrinology has been quite successful in describing this variation among and within species, but we have only just begun to understand how these factors interact to affect phenotypic diversity, ecological function, and evolution. Mounting evidence suggests that various molecular epigenetic modifications of genome structure and activity, such as deoxyribonucleic acid methylation, histone modifications, non-coding RNAs, and small RNAs, mediate the interactions between environmental conditions, individual traits, and the endocrine system. As some epigenetic modifications can be induced or removed by environmental stimuli, they represent promising candidates underlying endocrine regulation and variation, particularly epigenetic marks that can be stably inherited. This symposium discussed the role of epigenetic modifications in endocrine systems, mainly in natural populations.

2D Solid-State Nanopore Field-Effect Transistors: Comprehensive Computational Methodology for Biosensing Applications

State-of-the-Art technologies for the implementation of solid-state nanopores for molecular biosensing are reviewed in this article, with an emphasis on the use of 2D material membranes. Specific advantages of these 2D materials are their ability to read biomolecular information by electronic current variations along the nanoporous membranes. This review outlines a comprehensive computational approach combining molecular dynamics with semiconductor modeling and statistical signal processing to analyze the detailed interaction between biomolecules and solid-state nanopores. The technique is illustrated with three important biomedical applications, i.e., deoxyribonucleic acid (DNA) sequencing, epigenetic detection of DNA methylation, and identification of backbone breakage sites along double strand DNA (dsDNA).

Differences of DNA methylation patterns in the placenta of large for gestational age infant

To investigate the molecular mechanisms of later metabolic health changes in large for gestational age (LGA) newborns by analyzing deoxyribonucleic acid (DNA) methylation patterns in the placenta of LGA and appropriate for gestational age (AGA) newborns.A total of 6 placentas of LGA and 6 placentas of AGA newborns were enrolled as LGA group and AGA group. DNA methylation was analyzed using the Illumina Infinium Human MethylationEPIC BeadChip microarrays and verified via pyrosequencing and reverse transcription-quantitative real-time polymerase chain reaction. Functional enrichment analysis were constructed by gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis based on the differentially methylated regions between LGA and AGA groups.Clinical investigation showed that LGA newborns had significantly lower hemoglobin and blood glucose compared to AGA newborns. Birth weight was negatively correlated to hemoglobin and blood glucose. Genome-wide DNA methylation analysis identified 17 244 methylation variable positions achieving genome-wide significance (adjusted P < .05). 34% methylation variable positions were located in the gene promoter region. A total of 117 differentially methylated regions were revealed by bump hunting analysis, which mapped to 107 genes. Function analysis showed 13 genes enriched in "adhesion and infection process, endocrine and other factor-regulated calcium reabsorption, calcium signaling pathway and transmembrane transport". Four genes linked to type II diabetes mellitus. Among the 13 genes, we selected GNAS and calcium voltage-gated channel subunit alpha1 G for independent verification of pyrosequencing, and the messenger ribonucleic acid levels of guanine nucleotide binding protein, calcium voltage-gated channel subunit alpha1 G, DECR1, and FK506 binding protein 11 were verified by reverse transcription-quantitative real-time polymerase chain reaction.DNA methylation variation and gene expression differences in placental samples were associated with LGA newborns, which linking the effect of intrauterine environment to regulation of the offspring's gene expression. Furthermore, pathway analysis suggested that intrauterine environment affecting fetal growth might had a functional impact on multiple signaling pathways involved in fetal growth, metabolism, and inflammation. Further studies were required to understand the differences of methylation patterns.

Nanoparticle-based Drug Delivery Systems for Targeted Epigenetics Cancer Therapy

This review summarizes the epigenetic mechanisms of deoxyribonucleic acid (DNA) methylation, histone modifications in cancer and the epigenetic modifications in cancer therapy. Due to their undesired side effects, the use of epigenetic drugs as chemo-drugs in cancer therapies is limited. The drug delivery system opens a door for minimizing these side effects and achieving greater therapeutic benefits. The limitations of current epigenetic therapies in clinical cancer treatment and the advantages of using drug delivery systems for epigenetic agents are also discussed. Combining drug delivery systems with epigenetic therapy is a promising approach to reaching a high therapeutic index and minimizing the side effects.

Epigenetic modification and therapeutic targets of diabetes mellitus.

The prevalence of diabetes and its related complications are increasing significantly globally. Collected evidence suggested that several genetic and environmental factors contribute to diabetes mellitus. Associated complications such as retinopathy, neuropathy, nephropathy and other cardiovascular complications are a direct result of diabetes. Epigenetic factors include deoxyribonucleic acid (DNA) methylation and histone post-translational modifications. These factors are directly related with pathological factors such as oxidative stress, generation of inflammatory mediators and hyperglycemia. These result in altered gene expression and targets cells in the pathology of diabetes mellitus without specific changes in a DNA sequence. Environmental factors and malnutrition are equally responsible for epigenetic states. Accumulated evidence suggested that environmental stimuli alter the gene expression that result in epigenetic changes in chromatin. Recent studies proposed that epigenetics may include the occurrence of ‘metabolic memory’ found in animal studies. Further study into epigenetic mechanism might give us new vision into the pathogenesis of diabetes mellitus and related complication thus leading to the discovery of new therapeutic targets. In this review, we discuss the possible epigenetic changes and mechanism that happen in diabetes mellitus type 1 and type 2 separately. We highlight the important epigenetic and non-epigenetic therapeutic targets involved in the management of diabetes and associated complications.

Deoxyribonucleic acid (DNA) methylation in children exposed to air pollution: a possible mechanism underlying respiratory health effects development.

Air pollution is a substantial environmental threat to children and acts as acute and chronic disease risk factors alike. Several studies have previously evaluated epigenetic modifications concerning its exposure across various life stages. However, findings on epigenetic modifications as the consequences of air pollution during childhood are rather minimal. This review evaluated highly relevant studies in the field to analyze the existing literature regarding exposure to air pollution, with a focus on epigenetic alterations during childhood and their connections with respiratory health effects. The search was conducted using readily available electronic databases (PubMed and ScienceDirect) to screen for children's studies on epigenetic mechanisms following either pre- or post-natal exposure to air pollutants. Studies relevant enough and matched the predetermined criteria were chosen to be reviewed. Non-English articles and studies that did not report both air monitoring and epigenetic outcomes in the same article were excluded. The review found that epigenetic changes have been linked with exposure to air pollutants during early life with evidence and reports of how they may deregulate the epigenome balance, thus inducing disease progression in the future. Epigenetic studies evolve as a promising new approach in deciphering the underlying impacts of air pollution on deoxyribonucleic acid (DNA) due to links established between some of these epigenetic mechanisms and illnesses.

Effects of mineral methionine hydroxy analog chelate in sow diets on epigenetic modification and growth of progeny.

The study was conducted to determine the effects of mineral methionine hydroxy analog chelate (MMHAC) partially replacing inorganic trace minerals in sow diets on epigenetic and transcriptional changes in the muscle and jejunum of progeny. The MMHAC is zinc (Zn), manganese (Mn), and copper (Cu) chelated with methionine hydroxy analog (Zn-, Mn-, and Cu-methionine hydroxy analog chelate [MHAC]). On day 35 of gestation, 60 pregnant sows were allotted to two dietary treatments in a randomized completed block design using parity as a block: 1) ITM: inorganic trace minerals with zinc sulfate (ZnSO4), manganese oxide (MnO), and copper sulfate (CuSO4) and 2) CTM: 50% of ITM was replaced with MMHAC (MINTREX trace minerals, Novus International Inc., St Charles, MO). Gestation and lactation diets were formulated to meet or exceed NRC requirements. On days 1 and 18 of lactation, milk samples from 16 sows per treatment were collected to measure immunoglobulins (immunoglobulin G, immunoglobulin A, and immunoglobulin M) and micromineral concentrations. Two pigs per litter were selected to collect blood to measure the concentration of immunoglobulins in the serum, and then euthanized to collect jejunal mucosa, jejunum tissues, and longissimus muscle to measure global deoxyribonucleic acid methylation, histone acetylation, cytokines, and jejunal histomorphology at birth and day 18 of lactation. Data were analyzed using Proc MIXED of SAS. Supplementation of MMHAC tended to decrease (P = 0.059) body weight (BW) loss of sows during lactation and tended to increase (P = 0.098) piglet BW on day 18 of lactation. Supplementation of MMHAC increased (P < 0.05) global histone acetylation and tended to decrease myogenic regulatory factor 4 messenger ribonucleic acid (mRNA; P = 0.068) and delta 4-desaturase sphingolipid1 (DEGS1) mRNA (P = 0.086) in longissimus muscle of piglets at birth. Supplementation of MMHAC decreased (P < 0.05) nuclear factor kappa B mRNA in the jejunum and DEGS1 mRNA in longissimus muscle and tended to decrease mucin-2 (MUC2) mRNA (P = 0.057) and transforming growth factor-beta 1 (TGF-β1) mRNA (P = 0.057) in the jejunum of piglets on day 18 of lactation. There were, however, no changes in the amounts of tumor necrosis factor-alpha, interleukin-8, TGF-β, MUC2, and myogenic factor 6 in the tissues by MMHAC. In conclusion, maternal supplementation of MMHAC could contribute to histone acetylation and programming in the fetus, which potentially regulates intestinal health and skeletal muscle development of piglets at birth and weaning, possibly leading to enhanced growth of their piglets.