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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 -
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 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 -
International Journal of Molecular... Apr 2023This systematic review and meta-analysis summarize the difference in the methylation of the gene in patients with abnormal versus normal conventional sperm parameters.... (Meta-Analysis)
Meta-Analysis Review
This systematic review and meta-analysis summarize the difference in the methylation of the gene in patients with abnormal versus normal conventional sperm parameters. It also evaluates the effects of age and sperm concentration on methylation in spermatozoa using meta-regression analysis. It was performed according to the MOOSE guidelines for meta-analyses and Systematic Reviews of Observational Studies and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). The quality of the evidence reported in the studies included was assessed using the Cambridge Quality Checklists. A total of 11 articles met our inclusion criteria. Quantitative analysis showed that methylation levels were significantly lower in the group of infertile patients than in fertile controls. The reduction in methylation was much more pronounced in patients with oligozoospermia (alone or associated with other sperm parameter abnormalities) and in those with recurrent pregnancy loss. Meta-regression analysis showed the results to be independent of both patient age and sperm concentration. Therefore, the methylation pattern should be evaluated among couples accessing assisted reproductive techniques (ART), in order to gain prognostic information on ART outcome and offspring health.
Topics: Female; Humans; Male; Pregnancy; DNA Methylation; Genomic Imprinting; Histones; Infertility, Male; Meta-Analysis as Topic; Semen; Spermatozoa
PubMed: 37108386
DOI: 10.3390/ijms24087224 -
Clinical Epigenetics Mar 2023Cardiovascular disease (CVD) is the leading cause of death worldwide and considered one of the most environmentally driven diseases. The role of DNA methylation in... (Review)
Review
BACKGROUND
Cardiovascular disease (CVD) is the leading cause of death worldwide and considered one of the most environmentally driven diseases. The role of DNA methylation in response to the individual exposure for the development and progression of CVD is still poorly understood and a synthesis of the evidence is lacking.
RESULTS
A systematic review of articles examining measurements of DNA cytosine methylation in CVD was conducted in accordance with PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. The search yielded 5,563 articles from PubMed and CENTRAL databases. From 99 studies with a total of 87,827 individuals eligible for analysis, a database was created combining all CpG-, gene- and study-related information. It contains 74,580 unique CpG sites, of which 1452 CpG sites were mentioned in ≥ 2, and 441 CpG sites in ≥ 3 publications. Two sites were referenced in ≥ 6 publications: cg01656216 (near ZNF438) related to vascular disease and epigenetic age, and cg03636183 (near F2RL3) related to coronary heart disease, myocardial infarction, smoking and air pollution. Of 19,127 mapped genes, 5,807 were reported in ≥ 2 studies. Most frequently reported were TEAD1 (TEA Domain Transcription Factor 1) and PTPRN2 (Protein Tyrosine Phosphatase Receptor Type N2) in association with outcomes ranging from vascular to cardiac disease. Gene set enrichment analysis of 4,532 overlapping genes revealed enrichment for Gene Ontology molecular function "DNA-binding transcription activator activity" (q = 1.65 × 10) and biological processes "skeletal system development" (q = 1.89 × 10). Gene enrichment demonstrated that general CVD-related terms are shared, while "heart" and "vasculature" specific genes have more disease-specific terms as PR interval for "heart" or platelet distribution width for "vasculature." STRING analysis revealed significant protein-protein interactions between the products of the differentially methylated genes (p = 0.003) suggesting that dysregulation of the protein interaction network could contribute to CVD. Overlaps with curated gene sets from the Molecular Signatures Database showed enrichment of genes in hemostasis (p = 2.9 × 10) and atherosclerosis (p = 4.9 × 10).
CONCLUSION
This review highlights the current state of knowledge on significant relationship between DNA methylation and CVD in humans. An open-access database has been compiled of reported CpG methylation sites, genes and pathways that may play an important role in this relationship.
Topics: Humans; DNA Methylation; Cardiovascular Diseases; CpG Islands; Smoking; Air Pollution; Epigenesis, Genetic
PubMed: 36991458
DOI: 10.1186/s13148-023-01468-y -
Archives of Public Health = Archives... Jun 2022Epigenetic changes, especially DNA methylation have a main role in regulating cardiometabolic disorders and their risk factors. This study provides a review of the... (Review)
Review
BACKGROUND
Epigenetic changes, especially DNA methylation have a main role in regulating cardiometabolic disorders and their risk factors. This study provides a review of the current evidence on the association between methylation of some genes (LINE1, ABCG1, SREBF1, PHOSPHO1, ADRB3, and LEP) and cardiometabolic risk factors.
METHODS
A systematic literature search was conducted in electronic databases including Web of Science, PubMed, EMBASE, Google Scholar and Scopus up to end of 2020. All observational human studies (cross-sectional, case-control, and cohort) were included. Studies that assessed the effect of DNA methylation on cardiometabolic risk factors were selected.
RESULTS
Among 1398 articles, eight studies and twenty-one studies were included in the meta-analysis and the systematic review, respectively. Our study showed ABCG1 and LINE1 methylation were positively associated with blood pressure (Fisher's zr = 0.07 (0.06, 0.09), 95% CI: 0.05 to 0.08). Methylation in LINE1, ABCG1, SREBF1, PHOSPHO1 and ADRB3 had no significant association with HDL levels (Fisher's zr = - 0.05 (- 0.13, 0.03), 95% CI:-0.12 to 0.02). Positive association was existed between LINE1, ABCG1 and LEP methylation and LDL levels (Fisher's zr = 0.13 (0.04, 0.23), 95% CI: 0.03 to 0.23). Moreover, positive association was found between HbA1C and ABCG1 methylation (Fisher's zr = 0.11 (0.09, 0.13), 95% CI: 0.09 to 0.12). DNA methylation of LINE1, ABCG1 and SREBF1 genes had no significant association with glucose levels (Fisher's zr = 0.01 (- 0.12, 0.14), 95% CI:-0.12 to 0.14).
CONCLUSION
This meta-analysis showed that DNA methylation was associated with some cardiometabolic risk factors including LDL-C, HbA1C, and blood pressure.
REGISTRATION
Registration ID of the protocol on PROSPERO is CRD42020207677 .
PubMed: 35655232
DOI: 10.1186/s13690-022-00907-1 -
Psychosomatic Medicine Oct 2023Functional somatic syndromes (FSS) are highly prevalent across all levels of health care. The fact that they are characterized by medically unexplained symptoms, such as...
OBJECTIVE
Functional somatic syndromes (FSS) are highly prevalent across all levels of health care. The fact that they are characterized by medically unexplained symptoms, such as fatigue and pain, raises the important question of their underlying pathophysiology. Psychosocial stress represents a significant factor in the development of FSS and can induce long-term modifications at the epigenetic level. The aim of this review was to systematically review, for the first time, whether individuals with FSS are characterized by specific alterations in DNA methylation.
METHODS
MEDLINE and PsycINFO were searched from the first available date to September 2022. The inclusion criteria were as follows: a) adults fulfilling the research diagnostic criteria for chronic fatigue syndrome, fibromyalgia syndrome, and/or irritable bowel syndrome; b) healthy control group; and c) candidate-gene or genome-wide study of DNA methylation.
RESULTS
Sixteen studies ( N = 957) were included. In candidate-gene studies, specific sites within NR3C1 were identified, which were hypomethylated in individuals with chronic fatigue syndrome compared with healthy controls. In genome-wide studies in chronic fatigue syndrome, a hypomethylated site located to LY86 and hypermethylated sites within HLA-DQB1 were found. In genome-wide studies in fibromyalgia syndrome, differential methylation in sites related to HDAC4 , TMEM44 , KCNQ1 , SLC17A9 , PRKG1 , ALPK3 , TFAP2A , and LY6G5C was found.
CONCLUSIONS
Individuals with chronic fatigue syndrome and fibromyalgia syndrome seem to be characterized by altered DNA methylation of genes regulating cellular signaling and immune functioning. In chronic fatigue syndrome, there is preliminary evidence for these to be implicated in key pathophysiological alterations, such as hypocortisolism and low-grade inflammation, and to contribute to the debilitating symptoms these individuals experience.
PREREGISTRATION
PROSPERO identifier: CRD42022364720.
Topics: Adult; Humans; Fatigue Syndrome, Chronic; Fibromyalgia; DNA Methylation; Genome-Wide Association Study; Irritable Bowel Syndrome
PubMed: 37531610
DOI: 10.1097/PSY.0000000000001237 -
International Journal of Molecular... May 2023Autism spectrum disorder (ASD) is a complex neurodevelopmental condition, the underlying pathological mechanisms of which are not yet completely understood. Although... (Review)
Review
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition, the underlying pathological mechanisms of which are not yet completely understood. Although several genetic and genomic alterations have been linked to ASD, for the majority of ASD patients, the cause remains unknown, and the condition likely arises due to complex interactions between low-risk genes and environmental factors. There is increasing evidence that epigenetic mechanisms that are highly sensitive to environmental factors and influence gene function without altering the DNA sequence, particularly aberrant DNA methylation, are involved in ASD pathogenesis. This systematic review aimed to update the clinical application of DNA methylation investigations in children with idiopathic ASD, investigating its potential application in clinical settings. To this end, a literature search was performed on different scientific databases using a combination of terms related to the association between peripheral DNA methylation and young children with idiopathic ASD; this search led to the identification of 18 articles. In the selected studies, DNA methylation is investigated in peripheral blood or saliva samples, at both gene-specific and genome-wide levels. The results obtained suggest that peripheral DNA methylation could represent a promising methodology in ASD biomarker research, although further studies are needed to develop DNA-methylation-based clinical applications.
Topics: Humans; Child; Child, Preschool; DNA Methylation; Autism Spectrum Disorder; Epigenesis, Genetic; Biomarkers; Phenotype
PubMed: 37298088
DOI: 10.3390/ijms24119138 -
EBioMedicine May 2024This study investigates the associations between air pollution and colorectal cancer (CRC) risk and survival from an epigenomic perspective. (Meta-Analysis)
Meta-Analysis
BACKGROUND
This study investigates the associations between air pollution and colorectal cancer (CRC) risk and survival from an epigenomic perspective.
METHODS
Using a newly developed Air Pollutants Exposure Score (APES), we utilized a prospective cohort study (UK Biobank) to investigate the associations of individual and combined air pollution exposures with CRC incidence and survival, followed by an up-to-date systematic review with meta-analysis to verify the associations. In epigenetic two-sample Mendelian randomization analyses, we examine the associations between genetically predicted DNA methylation related to air pollution and CRC risk. Further genetic colocalization and gene-environment interaction analyses provided different insights to disentangle pathogenic effects of air pollution via epigenetic modification.
FINDINGS
During a median 12.97-year follow-up, 5767 incident CRC cases among 428,632 participants free of baseline CRC and 533 deaths in 2401 patients with CRC were documented in the UK Biobank. A higher APES score was associated with an increased CRC risk (HR, 1.03, 95% CI = 1.01-1.06; P = 0.016) and poorer survival (HR, 1.13, 95% CI = 1.03-1.23; P = 0.010), particularly among participants with insufficient physical activity and ever smokers (P > 0.05). A subsequent meta-analysis of seven observational studies, including UK Biobank data, corroborated the association between PM exposure (per 10 μg/m increment) and elevated CRC risk (RR,1.42, 95% CI = 1.12-1.79; P = 0.004; I = 90.8%). Genetically predicted methylation at PM-related CpG site cg13835894 near TMBIM1/PNKD and cg16235962 near CXCR5, and NO-related cg16947394 near TMEM110 were associated with an increased CRC risk. Gene-environment interaction analysis confirmed the epigenetic modification of aforementioned CpG sites with CRC risk and survival.
INTERPRETATION
Our study suggests the association between air pollution and CRC incidence and survival, underscoring the possible modifying roles of epigenomic factors. Methylation may partly mediate pathogenic effects of air pollution on CRC, with annotation to epigenetic alterations in protein-coding genes TMBIM1/PNKD, CXCR5 and TMEM110.
FUNDING
Xue Li is supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001), the National Nature Science Foundation of China (No. 82204019) and Healthy Zhejiang One Million People Cohort (K-20230085). ET is supported by a Cancer Research UK Career Development Fellowship (C31250/A22804). MGD is supported by the MRC Human Genetics Unit Centre Grant (U127527198).
Topics: Aged; Female; Humans; Male; Middle Aged; Air Pollutants; Air Pollution; Colorectal Neoplasms; DNA Methylation; Environmental Exposure; Epigenesis, Genetic; Epigenomics; Gene-Environment Interaction; Incidence; Mendelian Randomization Analysis; Prospective Studies; Risk Factors
PubMed: 38631091
DOI: 10.1016/j.ebiom.2024.105126 -
Psychiatry Research Jan 2022Schizophrenia has a large disease burden globally. Early intervention in psychosis, and therefore a decreased duration of untreated psychosis, has a positive clinical... (Review)
Review
BACKGROUND
Schizophrenia has a large disease burden globally. Early intervention in psychosis, and therefore a decreased duration of untreated psychosis, has a positive clinical impact. There are several recognized risk factors for psychosis, including trauma history and substance use. This systematic review examined the literature for studies related to epigenetic changes in first-episode psychosis, with the goal of identifying future research directions.
METHODS
A literature review was conducted from inception to October 3, 2021 using MedLine/PubMed, Web of Science, and PsycInfo searches with the keywords ("first-episode schizophrenia" OR "first-episode psychosis" OR "drug-naive schizophrenia" OR "drug-naive psychosis") AND (epigenetic OR methylation OR hydroxymethylation OR "histone modification" OR "miRNA") as well as a search of the bibliography of the identified papers.
RESULTS
Seventeen studies that examined various portions of the genome were included in this systematic review. There were two studies that showed hypomethylation at the LINE-1 portion of the genome and two that showed hypermethylation at LINE-1. Additionally, two studies showed hypomethylation specifically at the GRIN2B promoter (part of LINE-1).
CONCLUSIONS
Although sample sizes were small, these studies provide evidence for epigenetic alterations in early psychosis. Further research in this area is warranted for more definitive epigenetic correlations.
Topics: DNA Methylation; Epigenesis, Genetic; Humans; Promoter Regions, Genetic; Psychotic Disorders; Schizophrenia
PubMed: 34896847
DOI: 10.1016/j.psychres.2021.114325