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Biochimica Et Biophysica Acta.... Jan 2023DNA methylation profiles are in dynamic equilibrium via the initiation of methylation, maintenance of methylation and demethylation, which control gene expression and... (Review)
Review
DNA methylation profiles are in dynamic equilibrium via the initiation of methylation, maintenance of methylation and demethylation, which control gene expression and chromosome stability. Changes in DNA methylation patterns play important roles in carcinogenesis and primarily manifests as hypomethylation of the entire genome and the hypermethylation of individual loci. These changes may be reflected in blood-based DNA, which provides a non-invasive means for cancer monitoring. Previous blood-based DNA detection objects primarily included circulating tumor DNA/cell-free DNA (ctDNA/cfDNA), circulating tumor cells (CTCs) and exosomes. Researchers gradually found that methylation changes in peripheral blood mononuclear cells (PBMCs) also reflected the presence of tumors. Blood-based DNA methylation is widely used in early diagnosis, prognosis prediction, dynamic monitoring after treatment and other fields of clinical research on cancer. The reversible methylation of genes also makes them important therapeutic targets. The present paper summarizes the changes in DNA methylation in cancer based on existing research and focuses on the characteristics of the detection objects of blood-based DNA, including ctDNA/cfDNA, CTCs, exosomes and PBMCs, and their application in clinical research.
Topics: Humans; DNA Methylation; Leukocytes, Mononuclear; Biomarkers, Tumor; Circulating Tumor DNA; Neoplasms; Cell-Free Nucleic Acids
PubMed: 36270476
DOI: 10.1016/j.bbadis.2022.166583 -
Neuroscience and Biobehavioral Reviews Jul 2019Environmental stressors, such as childhood maltreatment, have been recognized to contribute to the development of depression. Growing evidence suggests that epigenetic...
Environmental stressors, such as childhood maltreatment, have been recognized to contribute to the development of depression. Growing evidence suggests that epigenetic changes are a key mechanism by which stressors interact with the genome leading to stable changes in DNA structure, gene expression, and behaviour. The current review aimed to evaluate the relationship between stress-associated epigenetic changes and depression. Human studies were identified via systematic searching of PubMed/Medline from inception to February 2018. Seventeen articles were identified. Stress-associated epigenetic changes in the following genes were correlated with depression: NRC31, SLCA4, BDNF, FKBP5, SKA2, OXTR, LINGO3, POU3F1 and ITGB1. Epigenetic changes in glucocorticoid signaling (e.g., NR3C1, FKBP5), serotonergic signaling (e.g. SLC6A4), and neurotrophin (e.g., BDNF) genes appear to be the most promising therapeutic targets for future research. However, continued research is warranted due to inconsistent findings regarding the directionality of epigenetic modification. Future studies should also aim to control for the use of psychotropic agents due to their widespread use in depressed populations and established effects on DNA methylation.
Topics: Adult; Adverse Childhood Experiences; Child; Child Abuse; Depression; Depressive Disorder, Major; Epigenesis, Genetic; Humans; Stress, Psychological
PubMed: 31005627
DOI: 10.1016/j.neubiorev.2019.04.010 -
Neuroscience and Biobehavioral Reviews Apr 2023Child maltreatment (CM) encompasses sexual abuse, physical abuse, emotional abuse, neglect, and exposure to domestic and family violence. Epigenetic research... (Review)
Review
Child maltreatment (CM) encompasses sexual abuse, physical abuse, emotional abuse, neglect, and exposure to domestic and family violence. Epigenetic research investigating CM has focused on differential DNA methylation (DNAm) in genes associated with the stress response, but there has been limited evaluation of the specific effects of subtypes of CM. This systematic review of literature investigating DNAm associated with CM in non-clinical populations aimed to summarise the approaches currently used in research, how the type of maltreatment and age of exposure were encoded via methylation, and which genes have consistently been associated with CM. A total of fifty-four papers were eligible for review, including forty-one candidate gene studies, eight epigenome-wide association studies, and five studies with a mixed design. The ways in which the various forms of CM were conceptualised and measured varied between papers. Future studies would benefit from assessments that employ conceptually robust definitions of CM, and that capture important contextual information such as age of exposure and subtype of CM.
Topics: Child; Humans; DNA Methylation; Child Abuse
PubMed: 36764637
DOI: 10.1016/j.neubiorev.2023.105079 -
Clinical Epigenetics Feb 2023Patients diagnosed with epithelial ovarian cancer (OC) have a 5-year survival rate of 49%. For early-stage disease, the 5-year survival rate is above 90%. However,... (Review)
Review
Patients diagnosed with epithelial ovarian cancer (OC) have a 5-year survival rate of 49%. For early-stage disease, the 5-year survival rate is above 90%. However, advanced-stage disease accounts for most cases as patients with early stages often are asymptomatic or present with unspecific symptoms, highlighting the need for diagnostic tools for early diagnosis. Liquid biopsy is a minimal invasive blood-based approach that utilizes circulating tumor DNA (ctDNA) shed from tumor cells for real-time detection of tumor genetics and epigenetics. Increased DNA methylation of promoter regions is an early event during tumorigenesis, and the methylation can be detected in ctDNA, accentuating the promise of methylated ctDNA as a biomarker for OC diagnosis. Many studies have investigated multiple methylation biomarkers in ctDNA from plasma or serum for discriminating OC patients from patients with benign diseases of the ovaries and/or healthy females. This systematic review summarizes and evaluates the performance of the currently investigated DNA methylation biomarkers in blood-derived ctDNA for early diagnosis of OC. PubMed's MEDLINE and Elsevier's Embase were systematically searched, and essential results such as methylation frequency of OC cases and controls, performance measures, as well as preanalytical factors were extracted. Overall, 29 studies met the inclusion criteria for this systematic review. The most common method used for methylation analysis was methylation-specific PCR, with half of the studies using plasma and the other half using serum. RASSF1A, BRCA1, and OPCML were the most investigated gene-specific methylation biomarkers, with OPCML having the best performance measures. Generally, methylation panels performed better than single gene-specific methylation biomarkers, with one methylation panel of 103,456 distinct regions and 1,116,720 CpGs having better performance in both training and validation cohorts. However, the evidence is still limited, and the promising methylation panels, as well as gene-specific methylation biomarkers highlighted in this review, need validation in large, prospective cohorts with early-stage asymptomatic OC patients to assess the true diagnostic value in a clinical setting.
Topics: Humans; Female; Cell-Free Nucleic Acids; DNA Methylation; Prospective Studies; Biomarkers, Tumor; Early Detection of Cancer; Ovarian Neoplasms; Cell Adhesion Molecules; GPI-Linked Proteins
PubMed: 36788585
DOI: 10.1186/s13148-023-01440-w -
Journal of Affective Disorders Apr 2023Growing evidence suggests that epigenetic modification is vital in biological processes of depression. Findings from studies exploring the associations between DNA... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Growing evidence suggests that epigenetic modification is vital in biological processes of depression. Findings from studies exploring the associations between DNA methylation and depression have been inconsistent.
METHODS
A systematical search of EMBASE, PubMed, Web of Science, and PsycINFO databases was conducted to include studies focusing on the associations between DNA methylation and depression (up to November 1st 2021) according to PRISMA guidelines with registration in PROSPERO (CRD42021288664).
RESULTS
A total of 47 studies met inclusion criteria and 31 studies were included in the meta-analysis. This meta-analysis found that genes hypermethylation, including BDNF (OR: 1.15, 95%CI: 1.01-1.32, I = 90 %), and NR3C1 (OR: 1.43, 95%CI: 1.09-1.87, I = 88 %) was associated with increased risk of depression. Significant association of SLC6A4 hypermethylation with depression was only found in the subgroup of using original data (OR: 1.09, 95%CI: 1.01-1.19, I = 52 %). BDNF hypermethylation could increase the risk of depression only in the Asian population (OR: 1.18, 95%CI: 1.01-1.40, I = 91 %), and significant associations of NR3C1 hypermethylation with depression were found in the group for depressive symptoms (OR: 1.34, 95%CI: 1.08-1.67, I = 85 %), but not for depressive disorder (OR: 1.89, 95%CI: 0.54-6.55, I = 94 %).
LIMITATIONS
More studies are needed to explore the factors that might influence the estimates owing to the contextual heterogeneity of the pooling of included studies.
CONCLUSIONS
It is noted that DNA hypermethylation, namely BDNF and NR3C1, is associated with increased risk of depression. The findings in this study could provide some material evidence for preventing and diagnosing of depression.
Topics: Humans; Brain-Derived Neurotrophic Factor; Depression; DNA Methylation; Epigenesis, Genetic; Serotonin Plasma Membrane Transport Proteins
PubMed: 36717033
DOI: 10.1016/j.jad.2023.01.079 -
Human Reproduction Update Aug 2022The many manipulations and processes used in ART coincide with the timing of epigenetic reprogramming and imprinting during female gametogenesis and pre-implantation... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The many manipulations and processes used in ART coincide with the timing of epigenetic reprogramming and imprinting during female gametogenesis and pre-implantation embryo development, leading to concerns that the actual ART could negatively affect epigenetic reprogramming and imprinting in gametes and early embryos. A growing body of literature suggests that ART may affect epigenetic marks, such as DNA methylation, in the fetus and placenta. Potentially, this may be responsible later in life for the increased risk of adverse outcomes associated with ART. Unfortunately, the conclusions are inconsistent and, despite the increasing usage of ART, its safety at the epigenetic level is still not established.
OBJECTIVE AND RATIONALE
To examine whether ART is associated with DNA methylation modifications and if these modifications persist throughout life, we provide an update on the current understanding of epigenetic reprogramming in human gametes and embryos, and then focus on the assessment of fetal and postnatal DNA methylation modifications that may remain until adulthood following the use of ART in humans.
SEARCH METHODS
We reviewed studies using targeted or epigenome-wide techniques to assess the DNA methylation patterns of the conceptus after ART compared with natural conceptions. A search for relevant studies was performed in the PubMed and EMBASE databases on 15 July 2021 with an extensive search equation. Studies on animals, gametes and embryos were subsequently excluded. After an in-depth review of full-text articles, studies on specific populations with imprinting disorders were removed and not further discussed. Before comprehensive analysis, the risk of bias of each included study was assessed with the Newcastle-Ottawa scale and quality of evidence was graded using the Grading of Recommendations, Assessment, Development and Evaluations criteria.
OUTCOMES
In total, 928 records were initially identified, and 51 were finally included in the systematic review. Given the variability in the genomic scale at which DNA methylation was measured in the different studies, they were separated into two categories: targeted DNA methylation or genome-wide DNA methylation study. The present systematic review has made it possible to assess a substantial number of children since more than 4000 DNA methylation profiles of ART concepti were compared to more than 7000 controls. There is evidence that ART conception is associated with aberrant DNA methylation in imprinted loci and other genes in various tissues. One isolated modification notably occur in the paternally expressed gene 1/mesoderm-specific transcript homologue (PEG1/MEST) region, and we cannot rule out other studied sequences owing to the heterogeneity of the evidence base.
WIDER IMPLICATIONS
Differences in DNA methylation after ART conceptions are modest, and the functional relevance in adult tissues is unknown. Functional effects in terms of gene expression as well as the roles of other epigenetic marks need to be further explored. Moreover, there is little overlap of findings obtained in targeted and genome-scale analyses owing to the lack of comparability of CpGs analyzed between both techniques. This issue also stems from small sample sizes and marked differences in methodology and cohort characteristics. Standardization of methodologies and large collaborative efforts are required to reduce the inconsistency of results and increase the robustness of findings. Finally, further studies are required to determine the contribution of parental infertility per se from the ART treatment.
Topics: Adult; Animals; Child; DNA; DNA Methylation; Female; Fertilization in Vitro; Genomic Imprinting; Humans; Infertility; Longevity; Pregnancy
PubMed: 35259267
DOI: 10.1093/humupd/dmac010 -
International Journal of Molecular... Aug 2022Background: Glioblastoma (GBM) is a highly aggressive cancer with poor prognosis that needs better treatment modalities. Moreover, there is a lack of reliable biomarkers... (Meta-Analysis)
Meta-Analysis Review
Background: Glioblastoma (GBM) is a highly aggressive cancer with poor prognosis that needs better treatment modalities. Moreover, there is a lack of reliable biomarkers to predict the response and outcome of current or newly designed therapies. While several molecular markers have been proposed as potential biomarkers for GBM, their uptake into clinical settings is slow and impeded by marker heterogeneity. Detailed assessment of prognostic and predictive value for biomarkers in well-defined clinical trial settings, if available, is scattered throughout the literature. Here we conducted a systematic review and meta-analysis to evaluate the prognostic and predictive significance of clinically relevant molecular biomarkers in GBM patients. Material and methods: A comprehensive literature search was conducted to retrieve publications from 3 databases (Pubmed, Cochrane and Embase) from January 2010 to December 2021, using specific terms. The combined hazard ratios (HR) and confidence intervals (95% CI) were used to evaluate the association of biomarkers with overall survival (OS) in GBM patients. Results: Twenty-six out of 1831 screened articles were included in this review. Nineteen articles were included in the meta-analyses, and 7 articles were quantitatively summarised. Fourteen studies with 1231 GBM patients showed a significant association of MGMT methylation with better OS with the pooled HR of 1.66 (95% CI 1.32−2.09, p < 0.0001, random effect). Five studies including 541 GBM patients analysed for the prognostic significance of IDH1 mutation showed significantly better OS in patients with IDH1 mutation with a pooled HR of 2.37 (95% CI 1.81−3.12; p < 0.00001]. Meta-analysis performed on 5 studies including 575 GBM patients presenting with either amplification or high expression of EGFR gene did not reveal any prognostic significance with a pooled HR of 1.31 (95% CI 0.96−1.79; p = 0.08). Conclusions: MGMT promoter methylation and IDH1 mutation are significantly associated with better OS in GBM patients. No significant associations were found between EGFR amplification or overexpression with OS.
Topics: Biomarkers; Biomarkers, Tumor; Brain Neoplasms; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Glioblastoma; Humans; Tumor Suppressor Proteins
PubMed: 36012105
DOI: 10.3390/ijms23168835 -
Clinical Epigenetics May 2024DNA methylation influences gene expression and function in the pathophysiology of type 2 diabetes mellitus (T2DM). Mapping of T2DM-associated DNA methylation could aid...
OBJECTIVE
DNA methylation influences gene expression and function in the pathophysiology of type 2 diabetes mellitus (T2DM). Mapping of T2DM-associated DNA methylation could aid early detection and/or therapeutic treatment options for diabetics.
DESIGN
A systematic literature search for associations between T2DM and DNA methylation was performed. Prospero registration ID: CRD42020140436.
METHODS
PubMed and ScienceDirect databases were searched (till October 19, 2023). Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and New Castle Ottawa scale were used for reporting the selection and quality of the studies, respectively.
RESULT
Thirty-two articles were selected. Four of 130 differentially methylated genes in blood, adipose, liver or pancreatic islets (TXNIP, ABCG1, PPARGC1A, PTPRN2) were reported in > 1 study. TXNIP was hypomethylated in diabetic blood across ethnicities. Gene enrichment analysis of the differentially methylated genes highlighted relevant disease pathways (T2DM, type 1 diabetes and adipocytokine signaling). Three prospective studies reported association of methylation in IGFBP2, MSI2, FTO, TXNIP, SREBF1, PHOSPHO1, SOCS3 and ABCG1 in blood at baseline with incident T2DM/hyperglycemia. Sex-specific differential methylation was reported only for HOOK2 in visceral adipose tissue (female diabetics: hypermethylated, male diabetics: hypomethylated). Gene expression was inversely associated with methylation status in 8 studies, in genes including ABCG1 (blood), S100A4 (adipose tissue), PER2 (pancreatic islets), PDGFA (liver) and PPARGC1A (skeletal muscle).
CONCLUSION
This review summarizes available evidence for using DNA methylation patterns to unravel T2DM pathophysiology. Further validation studies in diverse populations will set the stage for utilizing this knowledge for identifying early diagnostic markers and novel druggable pathways.
Topics: Female; Humans; Male; Carrier Proteins; Diabetes Mellitus, Type 2; DNA Methylation; Epigenesis, Genetic
PubMed: 38755631
DOI: 10.1186/s13148-024-01670-6 -
Neuroscience and Biobehavioral Reviews May 2020DNA methylation (DNAm) - an epigenetic process that regulates gene expression - may represent a mechanism for the biological embedding of early traumatic experiences,...
DNA methylation (DNAm) - an epigenetic process that regulates gene expression - may represent a mechanism for the biological embedding of early traumatic experiences, including childhood maltreatment. Here, we conducted the first systematic review of human studies linking childhood maltreatment to DNAm. In total, 72 studies were included in the review (2008-2018). The majority of extant studies (i) were based on retrospective data in adults, (ii) employed a candidate gene approach (iii) focused on global maltreatment, (iv) were based on easily accessible peripheral tissues, typically blood; and (v) were cross-sectional. Two-thirds of studies (n = 48) also examined maltreatment-related outcomes, such as stress reactivity and psychiatric symptoms. While findings generally support an association between childhood maltreatment and altered patterns of DNAm, factors such as the lack of longitudinal data, low comparability across studies as well as potential genetic and 'pre-exposure' environmental confounding currently limit the conclusions that can be drawn. Key challenges are discussed and concrete recommendations for future research are provided to move the field forward.
Topics: Adult Survivors of Child Abuse; Adverse Childhood Experiences; DNA Methylation; Epigenesis, Genetic; Humans; Mental Disorders
PubMed: 32081689
DOI: 10.1016/j.neubiorev.2020.02.019 -
Journal of Crohn's & Colitis Mar 2023Over the past decade, the DNA methylome has been increasingly studied in peripheral blood of inflammatory bowel disease [IBD] patients. However, a comprehensive summary... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIMS
Over the past decade, the DNA methylome has been increasingly studied in peripheral blood of inflammatory bowel disease [IBD] patients. However, a comprehensive summary and meta-analysis of peripheral blood leukocyte [PBL] DNA methylation studies has thus far not been conducted. Here, we systematically reviewed all available literature up to February 2022 and summarized the observations by means of meta-analysis.
METHODS
We conducted a systematic search and critical appraisal of IBD-associated DNA methylation studies in PBL using the biomarker-based cross-sectional studies [BIOCROSS] tool. Subsequently, we performed meta-analyses on the summary statistics obtained from epigenome-wide association studies [EWAS] that included patients with Crohn's disease [CD], ulcerative colitis [UC] and/or healthy controls [HC].
RESULTS
Altogether, we included 15 studies for systematic review. Critical appraisal revealed large methodological and outcome heterogeneity between studies. Summary statistics were obtained from four studies based on a cumulative 552 samples [177 CD, 132 UC and 243 HC]. Consistent differential methylation was identified for 256 differentially methylated probes [DMPs; Bonferroni-adjusted p ≤ 0.05] when comparing CD with HC and 103 when comparing UC with HC. Comparing IBD [CD + UC] with HC resulted in 224 DMPs. Importantly, several of the previously identified DMPs, such as VMP1/TMEM49/MIR21 and RPS6KA2, were consistently differentially methylated across all studies.
CONCLUSION
Methodological homogenization of IBD epigenetic studies is needed to allow for easier aggregation and independent validation. Nonetheless, we were able to confirm previous observations. Our results can serve as the basis for future IBD epigenetic biomarker research in PBL.
Topics: Humans; DNA Methylation; Cross-Sectional Studies; Inflammatory Bowel Diseases; Crohn Disease; Colitis, Ulcerative; Membrane Proteins
PubMed: 35998097
DOI: 10.1093/ecco-jcc/jjac119