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International Journal of Molecular... Jan 2020Major depressive disorder (MDD) is the leading cause of disability worldwide and is associated with high rates of suicide and medical comorbidities. Current...
Major depressive disorder (MDD) is the leading cause of disability worldwide and is associated with high rates of suicide and medical comorbidities. Current antidepressant medications are suboptimal, as most MDD patients fail to achieve complete remission from symptoms. At present, clinicians are unable to predict which antidepressant is most effective for a particular patient, exposing patients to multiple medication trials and side effects. Since MDD's etiology includes interactions between genes and environment, the epigenome is of interest for predictive utility and treatment monitoring. Epigenetic mechanisms of antidepressant medications are incompletely understood. Differences in epigenetic profiles may impact treatment response. A systematic literature search yielded 24 studies reporting the interaction between antidepressants and eight genes (, , , , , ) and whole genome methylation. Methylation of certain sites within , , , , , and the whole genome was predictive of antidepressant response. Comparing DNA methylation in patients during depressive episodes, during treatment, in remission, and after antidepressant cessation would help clarify the influence of antidepressant medications on DNA methylation. Individuals' unique methylation profiles may be used clinically for personalization of antidepressant choice in the future.
Topics: Antidepressive Agents; DNA Methylation; Depressive Disorder, Major; Epigenesis, Genetic; Humans; Treatment Outcome
PubMed: 32012861
DOI: 10.3390/ijms21030826 -
Molecules (Basel, Switzerland) Nov 2021Peptides are characterized by their wide range of biological activity: they regulate functions of the endocrine, nervous, and immune systems. The mechanism of such...
Peptides are characterized by their wide range of biological activity: they regulate functions of the endocrine, nervous, and immune systems. The mechanism of such action of peptides involves their ability to regulate gene expression and protein synthesis in plants, microorganisms, insects, birds, rodents, primates, and humans. Short peptides, consisting of 2-7 amino acid residues, can penetrate into the nuclei and nucleoli of cells and interact with the nucleosome, the histone proteins, and both single- and double-stranded DNA. DNA-peptide interactions, including sequence recognition in gene promoters, are important for template-directed synthetic reactions, replication, transcription, and reparation. Peptides can regulate the status of DNA methylation, which is an epigenetic mechanism for the activation or repression of genes in both the normal condition, as well as in cases of pathology and senescence. In this context, one can assume that short peptides were evolutionarily among the first signaling molecules that regulated the reactions of template-directed syntheses. This situation enhances the prospects of developing effective and safe immunoregulatory, neuroprotective, antimicrobial, antiviral, and other drugs based on short peptides.
Topics: Animals; DNA Methylation; Epigenesis, Genetic; Histones; Humans; Peptides; Signal Transduction
PubMed: 34834147
DOI: 10.3390/molecules26227053 -
Lifestyle Genomics 2023DNA methylation patterns are directly associated with diverse metabolic disorders. The status of methyl-donor micronutrients has been associated with DNA methylation... (Meta-Analysis)
Meta-Analysis
BACKGROUND
DNA methylation patterns are directly associated with diverse metabolic disorders. The status of methyl-donor micronutrients has been associated with DNA methylation levels, and altered ingestion of folate, choline, betaine, B vitamins and methionine may impact genes both globally and at the level of promoter regions. Despite this, the role of methyl-donor micronutrient supplementation on DNA methylation profiles is currently unclear.
OBJECTIVES
The aims of this systematic review and meta-analysis were to identify and synthesize the evidence about methyl-donor nutrient supplementation on DNA methylation.
METHODS
A systematic literature search was performed in Medline, Embase, Scopus, and Web of Science databases with a combination of terms related to DNA methylation assessment, supplementation, and methyl-donor nutrients. Studies (in vitro, animal models, or human clinical trials) were included if DNA methylation levels after any kind of methyl-donor micronutrient supplementation or treatment was investigated. Studies were assessed for bias using Revised Cochrane risk-of-bias tool for randomized trials, risk-of-bias in Non-randomized Studies of Interventions or Systematic Review Centre for Laboratory Animal Experimentation tools. Data were extracted from studies measuring DNA methylation levels in any sample or tissue, following any kind of methyl-donor micronutrient supplementation or treatment. Separate random-effects meta-analyses were performed for animal model studies and human clinical trials that examined the effects of folic acid supplementation on DNA methylation.
RESULTS
Fifty-seven studies were included in this systematic review: 18 human clinical trials, 35 in animal model, and 4 in vitro studies. Concerning overall risk of bias, most of the studies were classified as "high risk" or "some concerns." Meta-analysis with meta-regression from studies in animal models showed that folic acid dose significantly affected DNA methylation and that high and very high doses showed increases in DNA methylation when compared to low doses. However, meta-analysis of human clinical trials showed that folic acid supplementation did not promote significant changes in DNA methylation when compared to placebo.
CONCLUSION
Folic acid supplementation may change global DNA methylation levels in animals supplemented with high, as compared to low, doses. Heterogeneity in studies and supplementation protocols make it difficult to establish clinical recommendations. However, these effects, even if small, might be of clinical importance in the management of patients with diseases related to DNA hypomethylation.
Topics: Humans; Animals; DNA Methylation; Folic Acid; Dietary Supplements; Vitamin B Complex; Micronutrients
PubMed: 37935134
DOI: 10.1159/000533193 -
Epigenetics Dec 2024Epigenetic modifications, including DNA methylation, are proposed mechanisms explaining the impact of parental exposures to foetal development and lifelong health.... (Review)
Review
Epigenetic modifications, including DNA methylation, are proposed mechanisms explaining the impact of parental exposures to foetal development and lifelong health. Micronutrients including folate, choline, and vitamin B provide methyl groups for the one-carbon metabolism and subsequent DNA methylation processes. Placental DNA methylation changes in response to one-carbon moieties hold potential targets to improve obstetrical care. We conducted a systematic review on the associations between one-carbon metabolism and human placental DNA methylation. We included 22 studies. Findings from clinical studies with minimal ErasmusAGE quality score 5/10 ( = 15) and studies ( = 3) are summarized for different one-carbon moieties. Next, results are discussed per study approach: (1) global DNA methylation ( = 9), (2) genome-wide analyses ( = 4), and (3) gene specific ( = 14). Generally, one-carbon moieties were not associated with global methylation, although conflicting outcomes were reported specifically for choline. Using genome-wide approaches, few differentially methylated sites associated with S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), or dietary patterns. Most studies taking a gene-specific approach indicated site-specific relationships depending on studied moiety and genomic region, specifically in genes involved in growth and development including , , and ; however, overlap between studies was low. Therefore, we recommend to further investigate the impact of an optimized one-carbon metabolism on DNA methylation and lifelong health.
Topics: Female; Humans; Pregnancy; DNA Methylation; Placenta; Genome-Wide Association Study; Folic Acid; S-Adenosylmethionine; Choline; Carbon
PubMed: 38484284
DOI: 10.1080/15592294.2024.2318516 -
International Journal of Colorectal... Feb 2021Methylated cell-free DNA in liquid biopsies are promising non-invasive biomarkers for colorectal cancer (CRC). Optimal markers would have high sensitivity and... (Review)
Review
PURPOSE
Methylated cell-free DNA in liquid biopsies are promising non-invasive biomarkers for colorectal cancer (CRC). Optimal markers would have high sensitivity and specificity for early detection of CRC and could be detected in more than one type of material from the patient. We systematically reviewed the literature on DNA methylation markers of colorectal cancer, detected in more than one type of material, regarding their potential as contributors to a panel for screening and follow-up of CRC.
METHODS
The databases MEDLINE, Web of Science, and Embase were systematically searched. Data extraction and review was performed by two authors independently. Agreement between methylation status in tissue and other materials (blood/stool/urine) was analyzed using the McNemar test and Cohen's kappa.
RESULTS
From the 51 included studies, we identified seven single markers with sensitivity ≥ 75% and specificity ≥ 90% for CRC. We also identified one promising plasma panel and two stool panels. The correspondence of methylation status was evaluated as very good for four markers, but only marginal for most of the other markers investigated (12 of 21).
CONCLUSION
The included studies reported only some of the variables and markers of interest and included few patients. Hence, a meta-analysis was not possible at this point. Larger, prospective studies must be designed to study the discordant detection of markers in tissue and liquid biopsies. When reporting their findings, such studies should use a standardized format.
Topics: Biomarkers, Tumor; Colorectal Neoplasms; DNA Methylation; Early Detection of Cancer; Humans; Prospective Studies
PubMed: 33030559
DOI: 10.1007/s00384-020-03757-x -
Medicine Apr 2023O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that maintains the stability of genetic information. MGMT is a strong prognostic biomarker in... (Meta-Analysis)
Meta-Analysis
BACKGROUND
O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that maintains the stability of genetic information. MGMT is a strong prognostic biomarker in patients with glioblastoma. However, the effect of its gene hypermethylation and expression on the survival rate of head and neck cancer (HNC) patients is still disputed. Therefore, we conducted a meta-analysis to evaluate the prognostic value of MGMT hypermethylation and expression in HNC patients.
METHODS
This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines and was registered at the International Prospective Register of Systematic Reviews (CRD42021274728). Literature related to the survival rate of HNC patients and MGMT was systematically searched in PubMed, Embase, The Cochrane Library and Web of Science electronic databases (published from inception to February 1, 2023). The association was evaluated by the combined hazard ratio (HR) and related 95% confidence interval (CI). Two authors independently screened all records and extracted the data. The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation system. All of the statistical tests used in this meta-analysis were conducted with Stata 12.0 software.
RESULTS
We included 5 studies with 564 HNC patients for the meta-analysis. All of the included patients were primary tumors and underwent surgical resection without prior radiotherapy or chemotherapy therapy. No significant heterogeneity was noted between MGMT and overall survival, MGMT and disease-free survival, and a fixed-effects model was used. HNC patients with MGMT hypermethylation and low expression had a poor prognosis, with pooled HR for overall survival (HR = 1.23, 95% CI: 1.10-1.38, P < .001) and disease-free survival (HR = 2.28, 95% CI: 1.45-3.58, P < .001). Subgroup analysis stratified by molecular abnormalities, such as hypermethylation or low expression, showed similar results. The insufficient number of trials included in our study encountered high risk of bias and may increase the deviation of the final meta-analysis results.
CONCLUSION
HNC patients with MGMT hypermethylation and low expression were more likely to exhibit poorer survival. MGMT hypermethylation and low expression can predict survival in patients with HNC.
Topics: Humans; Prognosis; DNA Methylation; O(6)-Methylguanine-DNA Methyltransferase; DNA Repair Enzymes; Head and Neck Neoplasms; DNA
PubMed: 37026932
DOI: 10.1097/MD.0000000000033472 -
Clinical Epigenetics Feb 2022Although kidney transplantation improves patient survival and quality of life, long-term results are hampered by both immune- and non-immune-mediated complications....
BACKGROUND
Although kidney transplantation improves patient survival and quality of life, long-term results are hampered by both immune- and non-immune-mediated complications. Current biomarkers of post-transplant complications, such as allograft rejection, chronic renal allograft dysfunction, and cutaneous squamous cell carcinoma, have a suboptimal predictive value. DNA methylation is an epigenetic modification that directly affects gene expression and plays an important role in processes such as ischemia/reperfusion injury, fibrosis, and alloreactive immune response. Novel techniques can quickly assess the DNA methylation status of multiple loci in different cell types, allowing a deep and interesting study of cells' activity and function. Therefore, DNA methylation has the potential to become an important biomarker for prediction and monitoring in kidney transplantation.
PURPOSE OF THE STUDY
The aim of this study was to evaluate the role of DNA methylation as a potential biomarker of graft survival and complications development in kidney transplantation. MATERIAL AND METHODS: A systematic review of several databases has been conducted. The Newcastle-Ottawa scale and the Jadad scale have been used to assess the risk of bias for observational and randomized studies, respectively.
RESULTS
Twenty articles reporting on DNA methylation as a biomarker for kidney transplantation were included, all using DNA methylation for prediction and monitoring. DNA methylation pattern alterations in cells isolated from different tissues, such as kidney biopsies, urine, and blood, have been associated with ischemia-reperfusion injury and chronic renal allograft dysfunction. These alterations occurred in different and specific loci. DNA methylation status has also proved to be important for immune response modulation, having a crucial role in regulatory T cell definition and activity. Research also focused on a better understanding of the role of this epigenetic modification assessment for regulatory T cells isolation and expansion for future tolerance induction-oriented therapies.
CONCLUSIONS
Studies included in this review are heterogeneous in study design, biological samples, and outcome. More coordinated investigations are needed to affirm DNA methylation as a clinically relevant biomarker important for prevention, monitoring, and intervention.
Topics: Biomarkers; DNA Methylation; Graft Rejection; Humans; Kidney Neoplasms; Kidney Transplantation; Risk Assessment
PubMed: 35130936
DOI: 10.1186/s13148-022-01241-7 -
BMC Genomics Mar 2022Environmental exposures in utero which modify DNA methylation may have a long-lasting impact on health and disease in offspring. We aimed to identify and replicate...
BACKGROUND
Environmental exposures in utero which modify DNA methylation may have a long-lasting impact on health and disease in offspring. We aimed to identify and replicate previously published genomic loci where DNA methylation changes are attributable to in utero exposures in the NutriGen birth cohort studies Alliance.
METHODS
We reviewed the literature to identify differentially methylated sites of newborn DNA which are associated with the following five traits of interest maternal diabetes, pre-pregnancy body mass index (BMI), diet during pregnancy, smoking, and gestational age. We then attempted to replicate these published associations in the Canadian Healthy Infant Longitudinal Development (CHILD) and the South Asian birth cohort (START) cord blood epigenome-wide data.
RESULTS
We screened 68 full-text articles and identified a total of 17 cord blood epigenome-wide association studies (EWAS) of the traits of interest. Out of the 290 CpG sites reported, 19 were identified in more than one study; all of them associated with maternal smoking. In CHILD and START EWAS, thousands of sites associated with gestational age were identified and maintained significance after correction for multiple testing. In CHILD, there was differential methylation observed for 8 of the published maternal smoking sites. No other traits tested (i.e., folate levels, gestational diabetes, birthweight) replicated in the CHILD or START cohorts.
CONCLUSIONS
Maternal smoking during pregnancy and gestational age are strongly associated with differential methylation in offspring cord blood, as assessed in the EWAS literature and our birth cohorts. There are a limited number of reported methylation sites associated in more than two independent studies related to pregnancy. Additional large studies of diverse populations with fine phenotyping are needed to produce robust epigenome-wide data in order to further elucidate the effect of intrauterine exposures on the infants' methylome.
Topics: Canada; DNA Methylation; Epigenome; Female; Fetal Blood; Genome-Wide Association Study; Humans; Infant, Newborn; Pregnancy
PubMed: 35305575
DOI: 10.1186/s12864-022-08451-6 -
Indian Journal of Dental Research :... 2014Oral squamous cell carcinoma (OSCC) is a common cancer world-wide that is highly lethal due to its recurrence and metastasis. Methylation is a common epigenetic... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Oral squamous cell carcinoma (OSCC) is a common cancer world-wide that is highly lethal due to its recurrence and metastasis. Methylation is a common epigenetic mechanism that leads to gene silencing in tumors and could be a useful biomarker in OSCC. The prevalence of P16, death-associated protein kinase (DAPK) and O6-methylguanine-DNA-methyltransferase (MGMT) promoter hypermethylation in OSCC has been evaluated for several years while the results remain controversial.
OBJECTIVE
The aim of this systematic review is to critically analyze and perform a meta-analysis on the various studies in the literature that have reported the promoter hypermethylation of P16, DAPK and MGMT genes in OSCC.
SEARCH STRATEGY
Articles were searched and selected through PubMed. Hand search from the relevant journals was also performed. Articles were reviewed and analyzed.
RESULTS
The estimated prevalence of P16 methylation was 43%, DAPK methylation was 39.7% and MGMT methylation was 39.8%. Heterogeneity in methylation prevalences and correlations with the clinical outcomes of the disease prevailed in various studies.
CONCLUSION
We can conclude from our systematic review that a higher prevalence of methylation of P16, DAPK and MGMT occur in OSCC. Further studies are required to substantiate the role of methylation of P16, DAPK and MGMT as a marker in OSCC.
Topics: Carcinoma, Squamous Cell; Cyclin-Dependent Kinase Inhibitor p16; DNA Methylation; Death-Associated Protein Kinases; Humans; Mouth Neoplasms; O(6)-Methylguanine-DNA Methyltransferase; Promoter Regions, Genetic
PubMed: 25728117
DOI: 10.4103/0970-9290.152208 -
Oncotarget Jan 2017Ten-eleven translocation (TET) enzymes catalyze the oxidation of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) and then to 5-formylcytosine (5-fC) and... (Meta-Analysis)
Meta-Analysis Review
Ten-eleven translocation (TET) enzymes catalyze the oxidation of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) and then to 5-formylcytosine (5-fC) and 5-carboxylcytosine (5-caC), resulting in genomic DNA demethylation. Decreased 5-hmC levels have been reported in a variety of cancers, and loss of 5-hmC might be considered an epigenetic hallmark of cancer. However, the prognostic value of decreased 5-hmC in cancers remain controversial. Here, a systematic review was performed by conducting an electronic search of PubMed, EMBASE, Web of Science and the Cochrane Library. Finally, ten studies with a total of 1736 patients with cancer were included in the present study. Negative/low 5-hmC levels were significantly associated with lymph node metastasis [OR=2.20, 95% CI=1.23-3.96, P=0.008] and advanced TNM stage [OR=2.89, 95% CI=1.21-6.92, P=0.017]. More importantly, negative/low 5-hmC levels were significantly associated with poor prognosis of cancer patients [overall survival: HR=1.76, 95% CI=1.41-2.11, P < 0.001; disease free survival: HR=1.28, 95% CI=0.60-1.96, P < 0.001]. The results of this meta-analysis indicate that decreased 5-hmC levels are an indicator of poor survival of cancer patients. Given variability related to ethnicity, cancer types and detection methods, additional well-designed studies with larger sample sizes are required to further confirm our findings.
Topics: 5-Methylcytosine; Cytosine; DNA Methylation; Humans; Lymphatic Metastasis; Neoplasms; Prognosis
PubMed: 27911867
DOI: 10.18632/oncotarget.13719