scholarly journals Grandmaternal smoking during pregnancy is associated with differential DNA methylation in their grandchildren

2021 ◽  
Author(s):  
Sarah Holmes Watkins ◽  
Yasmin Iles-Caven ◽  
Marcus Pembrey ◽  
Jean Golding ◽  
Matthew Suderman
Keyword(s):  
Dna Methylation ◽  
Binding Sites ◽  
Association Studies ◽  
Epidemiological Studies ◽  
Limited Evidence ◽  
Smoking During Pregnancy ◽  
Cpg Sites ◽  
Specific Effects ◽  
Imprinting Control Region ◽  
First Time

AbstractThe idea that information can be transmitted to subsequent generation(s) by epigenetic means has been studied for decades but remains controversial in humans. Epidemiological studies have established that grandparental exposures are associated with health outcomes in their grandchildren, often with sex-specific effects; however the mechanism of transmission is still unclear. We conducted Epigenome Wide Association Studies (EWAS) to test whether grandmaternal smoking during pregnancy is associated with altered DNA methylation (DNAm) in their adolescent grandchildren. We used data from a birth cohort, with discovery and replication datasets of 1225 and 708 individuals (respectively), aged 15-17 years, and tested replication in the same individuals at birth and 7 years. We show for the first time that DNAm at a small number of loci is associated with grandmaternal smoking in humans, and their locations in the genome suggest hypotheses of transmission. We observe and replicate sex-specific associations at two sites on the X chromosome, one located in an imprinting control region and both within transcription factor binding sites (TFBSs). In fact, we observe enrichment for TFBSs among the CpG sites with the strongest associations, suggesting that TFBSs may be a mechanism by which grandmaternal exposures influence offspring DNA methylation. There is limited evidence that these associations appear at earlier timepoints, so effects are not static throughout development. The implication of this work is that effects of smoking during pregnancy may induce DNAm changes in later generations and that these changes are often sex-specific, in line with observational associations.

scholarly journals Comparison of DNA Methylation Profiles of Hemostatic Genes between Liver Tissue and Peripheral Blood within Individuals

2020 ◽  
Author(s):  
Annelie Angerfors ◽  
Martina Olsson Lindvall ◽  
Björn Andersson ◽  
Staffan Nilsson ◽  
Marcela Davila Lopez ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Peripheral Blood ◽  
Liver Tissue ◽  
Association Studies ◽  
Epidemiological Studies ◽  
Methylation Pattern ◽  
Cpg Dinucleotides ◽  
Phenotypic Differences ◽  
Targeted Bisulfite Sequencing ◽  
Hemostatic Genes

AbstractDNA methylation has become increasingly recognized in the etiology of complex diseases, including thrombotic disorders. Blood is often collected in epidemiological studies for genotyping and has recently also been used to examine DNA methylation in epigenome-wide association studies. DNA methylation patterns are often tissue-specific, thus, peripheral blood may not accurately reflect the methylation pattern in the tissue of relevance. Here, we collected paired liver and blood samples concurrently from 27 individuals undergoing liver surgery. We performed targeted bisulfite sequencing for a set of 35 hemostatic genes primarily expressed in liver to analyze DNA methylation levels of >10,000 cytosine-phosphate-guanine (CpG) dinucleotides. We evaluated whether DNA methylation in blood could serve as a proxy for DNA methylation in liver at individual CpGs. Approximately 30% of CpGs were nonvariable and were predominantly hypo- (<25%) or hypermethylated (>70%) in both tissues. While blood can serve as a proxy for liver at these CpGs, the low variability renders these unlikely to explain phenotypic differences. We therefore focused on CpG sites with variable methylation levels in liver. The level of blood–liver tissue correlation varied widely across these variable CpGs; moderate correlations (0.5 ≤ r < 0.75) were detected for 6% and strong correlations (r ≥ 0.75) for a further 4%. Our findings indicate that it is essential to study the concordance of DNA methylation between blood and liver at individual CpGs. This paired blood–liver dataset is intended as a resource to aid interpretation of blood-based DNA methylation results.

scholarly journals DNA Methylation and Type 2 Diabetes: the Use of Mendelian Randomization to Assess Causality

2019 ◽  
Vol 7 (4) ◽  
pp. 191-207 ◽  
Author(s):  
Diana L. Juvinao-Quintero ◽  
Marie-France Hivert ◽  
Gemma C. Sharp ◽  
Caroline L. Relton ◽  
Hannah R. Elliott
Keyword(s):  
Type 2 Diabetes ◽  
Dna Methylation ◽  
Mendelian Randomization ◽  
Epidemiological Studies ◽  
Mendelian Randomisation ◽  
Cross Sectional ◽  
Epigenetic Markers ◽  
Cpg Sites ◽  
Disease Understanding

Abstract Purpose of Review This review summarises recent advances in the field of epigenetics in order to understand the aetiology of type 2 diabetes (T2D). Recent Findings DNA methylation at a number of loci has been shown to be robustly associated with T2D, including TXNIP, ABCG1, CPT1A, and SREBF1. However, due to the cross-sectional nature of many epidemiological studies and predominant analysis in samples derived from blood rather than disease relevant tissues, inferring causality is difficult. We therefore outline the use of Mendelian randomisation (MR) as one method able to assess causality in epigenetic studies of T2D. Summary Epidemiological studies have been fruitful in identifying epigenetic markers of T2D. Triangulation of evidence including utilisation of MR is essential to delineate causal from non-causal biomarkers of disease. Understanding the causality of epigenetic markers in T2D more fully will aid prioritisation of CpG sites as early biomarkers to detect disease or in drug development to target epigenetic mechanisms in order to treat patients.

scholarly journals Sex-specific DNA methylation differences in people exposed to polybrominated biphenyl

Epigenomics ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 757-770
Author(s):  
Sarah W Curtis ◽  
Sabrina A Gerkowicz ◽  
Dawayland O Cobb ◽  
Varun Kilaru ◽  
Metrecia L Terrell ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Health Risks ◽  
Binding Sites ◽  
Adverse Health Outcomes ◽  
Functional Regions ◽  
Specific Effects ◽  
False Discovery ◽  
Polybrominated Biphenyls ◽  
Polybrominated Biphenyl ◽  
Specific Health

Aim: Michigan residents were exposed to polybrominated biphenyls (PBBs) when it was accidentally added to the food supply. Highly exposed individuals report sex-specific health problems, but the underlying biological mechanism behind these different health risks is not known. Materials and methods: DNA methylation in blood from 381 women and 277 men with PBB exposure was analyzed with the MethylationEPIC BeadChip. Results: 675 CpGs were associated with PBBs levels in males, while only 17 CpGs were associated in females (false discovery rate <0.05). No CpGs were associated in both sexes. These CpGs were enriched in different functional regions and transcription factor binding sites in each sex. Conclusion: Exposure to PBBs may have sex-specific effects on the epigenome that may underlie sex-specific adverse health outcomes.

scholarly journals An epigenetic pathway approach to investigating associations between prenatal exposure to maternal mood disorder and newborn neurobehavior

2018 ◽  
Vol 30 (3) ◽  
pp. 881-890 ◽  
Author(s):  
Elisabeth Conradt ◽  
Daniel E. Adkins ◽  
Sheila E. Crowell ◽  
Catherine Monk ◽  
Michael S. Kobor
Keyword(s):  
Dna Methylation ◽  
Transcription Factor ◽  
Mood Disorder ◽  
Prenatal Exposure ◽  
Binding Sites ◽  
Association Studies ◽  
Epigenetic Mechanisms ◽  
Maternal Mood ◽  
Target Dna ◽  
Analytical Approaches

AbstractFollowing recent advances in behavioral and psychiatric epigenetics, researchers are increasingly using epigenetic methods to study prenatal exposure to maternal mood disorder and its effects on fetal and newborn neurobehavior. Despite notable progress, various methodological limitations continue to obscure our understanding of the epigenetic mechanisms underpinning prenatal exposure to maternal mood disorder on newborn neurobehavioral development. Here we detail this problem, discussing limitations of the currently dominant analytical approaches (i.e., candidate epigenetic and epigenome-wide association studies), then present a solution that retains many benefits of existing methods while minimizing their shortcomings: epigenetic pathway analysis. We argue that the application of pathway-based epigenetic approaches that target DNA methylation at transcription factor binding sites could substantially deepen our mechanistic understanding of how prenatal exposures influence newborn neurobehavior.

scholarly journals Large-scale integration of DNA methylation and gene expression array platforms

2021 ◽  
Author(s):  
Eva E Lancaster ◽  
Vladimir I Vladimirov ◽  
Brien P Riley ◽  
Joseph W Landry ◽  
Roxann Roberson-Nay ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Large Scale ◽  
Association Studies ◽  
Adolescent And Young Adult ◽  
Expression Array ◽  
Cpg Sites ◽  
Disease States ◽  
Large Scale Integration ◽  
Scale Integration

Epigenome-wide association studies (EWAS) aim to provide evidence that marks of DNA methylation (DNAm) have downstream consequences that can result in the development of human diseases. Although these methods have been successful in identifying DNAm patterns associated with disease states, any further characterization of etiologic mechanisms remains elusive. This knowledge gap does not originate from a lack of DNAm-trait associations, but rather stems from study design issues that affect the interpretability of EWAS results. Despite known limitations in predicting the function of a particular CpG site, most EWAS maintain the broad assumption that altered DNAm results in a concomitant change of transcription at the most proximal gene. This study integrated DNAm and gene expression (GE) measurements in two cohorts, the Adolescent and Young Adult Twin Study (AYATS) and the Pregnancy, Race, Environment, Genes (PREG) study, to improve the understanding of epigenomic regulatory mechanisms. CpG sites associated with GE in cis were enriched in areas of transcription factor binding and areas of intermediate-to-low CpG density. CpG sites associated with trans GE were also enriched in areas of known regulatory significance, including enhancer regions. These results highlight issues with restricting DNAm-transcript annotations to small genomic intervals and question the validity of assuming a canonical cis DNAm-GE pathway. Based on these findings, the interpretation of EWAS results is limited in studies without multi-omic support and further research should identify genomic regions in which GE-associated DNAm is overrepresented.

scholarly journals Using Genetic Burden Scores for Gene-by-Methylation Interaction Analysis on Metabolic Syndrome in African Americans

2019 ◽  
Vol 21 (3) ◽  
pp. 279-285
Author(s):  
Jacquelyn Y. Taylor ◽  
Erin B. Ware ◽  
Michelle L. Wright ◽  
Jennifer A. Smith ◽  
Sharon L. R. Kardia
Keyword(s):  
Metabolic Syndrome ◽  
Dna Methylation ◽  
Data Analysis ◽  
African Americans ◽  
Multiple Testing ◽  
African American Men ◽  
Interaction Analysis ◽  
Association Studies ◽  
Cpg Sites ◽  
Genetic Burden

With the rapid advancement of omics-based research, particularly big data such as genome- and epigenome-wide association studies that include extensive environmental and clinical variables, data analytics have become increasingly complex. Researchers face significant challenges regarding how to analyze multifactorial data and make use of the findings for clinical translation. The purpose of this article is to provide a scientific exemplar for use of genetic burden scores as a data analysis method for studies with both genotype and DNA methylation data in which the goal is to evaluate associations with chronic conditions such as metabolic syndrome (MetS). This study included 739 African American men and women from the Genetic Epidemiology Network of Arteriopathy Study who met diagnostic criteria for MetS and had available genetic and epigenetic data. Genetic burden scores for evaluated genes were not significant after multiple testing corrections, but DNA methylation at 2 CpG sites (dihydroorotate dehydrogenase cg22381196 pFDR = .014; CTNNA3 cg00132141 pFDR = .043) was significantly associated with MetS after controlling for multiple comparisons. Interactions between the marginally significant CpG sites and burden scores, however, were not significant. More work is required in this area to identify intermediate biological pathways influenced by environmental, genetic, and epigenetic variation that may explain the high prevalence of MetS among African Americans. This study does serve, however, as an example of the use of the genetic burden score as an alternative data analysis approach for complex studies involving the analysis of genetic and epigenetic data simultaneously.

scholarly journals NF-Y Regulates the Antisense Promoter, Bidirectional Silencing, and Differential Epigenetic Marks of theKcnq1Imprinting Control Region

2004 ◽  
Vol 279 (50) ◽  
pp. 52685-52693 ◽  
Author(s):  
Radha Raman Pandey ◽  
Michele Ceribelli ◽  
Prim B. Singh ◽  
Johan Ericsson ◽  
Roberto Mantovani ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Control Region ◽  
Binding Sites ◽  
Antisense Transcription ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Epigenetic Marks ◽  
Imprinting Control Region ◽  
Parent Of Origin ◽  
First Time

Antisense transcription has been shown to be one of the hierarchies that control gene expression in eukaryotes. Recently, we have documented that the mouseKcnq1imprinting control region (ICR) harbors bidirectional silencing property, and this feature is linked to an antisense RNA,Kcnq1ot1. In this investigation, using genomic footprinting, we have identified three NF-Y transcription factor binding sites appearing in a methylation-sensitive manner in theKcnq1ot1promoter. By employing a dominant negative mutant to the NF-Y transcription factor, we have shown that the NF-Y transcription factor positively regulates antisense transcription. Selective mutation of the conserved nucleotides in the NF-Y binding sites resulted in the loss of antisense transcription. The loss of antisense transcription from theKcnq1ot1promoter coincides with an enrichment in the levels of deacetylation and methylation at the lysine 9 residue of histone H3 and DNA methylation at the CpG residues, implying a crucial role for the NF-Y transcription factor in organizing the parent of origin-specific chromatin conformation in theKcnq1ICR. Parallel to the loss of antisense transcription, the loss of silencing of the flanking reporter genes was observed, suggesting that NF-Y-mediatedKcnq1ot1transcription is critical in the bidirectional silencing process of theKcnq1ICR. These data highlight the NF-Y transcription factor as a crucial regulator of antisense promoter-mediated bidirectional silencing and the parent of origin-specific epigenetic marks at theKcnq1ICR. More importantly, for the first time, we document that NF-Y is involved in maintaining the antisense promoter activity against strong silencing conditions.

scholarly journals Prenatal smoke effect on mouse offspring Igf1 promoter methylation from fetal stage to adulthood is organ and sex specific

2020 ◽  
Vol 318 (3) ◽  
pp. L549-L561
Author(s):  
Zhijun Zeng ◽  
Karolin F. Meyer ◽  
Khosbayar Lkhagvadorj ◽  
Wierd Kooistra ◽  
Marjan Reinders-Luinge ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Promoter Methylation ◽  
Large Scale ◽  
Developmental Stages ◽  
Association Studies ◽  
Inverse Correlation ◽  
Cpg Sites ◽  
Increased Risk ◽  
Organ Specific ◽  
Health And Disease

Prenatal smoke exposure (PSE) is associated with reduced birth weight, impaired fetal development, and increased risk for diseases later in life. Changes in DNA methylation may be involved, as multiple large-scale epigenome-wide association studies showed that PSE is robustly associated with DNA methylation changes in blood among offspring in early life. Insulin-like growth factor-1 (IGF1) is important in growth, differentiation, and repair processes after injury. However, no studies investigated the organ-specific persistence of PSE-induced methylation change of Igf1 into adulthood. Based on our previous studies on the PSE effect on Igf1 promoter methylation in fetal and neonatal mouse offspring, we now have extended our studies to adulthood. Our data show that basal Igf1 promoter methylation generally increased in the lung but decreased in the liver (except for 2 persistent CpG sites in both organs) across three different developmental stages. PSE changed Igf1 promoter methylation in all three developmental stages, which was organ and sex specific. The PSE effect was less pronounced in adult offspring compared with the fetal and neonatal stages. In addition, the PSE effect in the adult stage was more pronounced in the lung compared with the liver. For most CpG sites, an inverse correlation was found for promoter methylation and mRNA expression when the data of all three stages were combined. This was more prominent in the liver. Our findings provide additional evidence for sex- and organ-dependent prenatal programming, which supports the developmental origins of health and disease (DOHaD) hypothesis.

New variable selection strategy for analysis of high-dimensional DNA methylation data

2018 ◽  
Vol 16 (04) ◽  
pp. 1850010 ◽  
Author(s):  
Jiyun Choi ◽  
Kipoong Kim ◽  
Hokeun Sun
Keyword(s):  
Dna Methylation ◽  
Variable Selection ◽  
Group Structure ◽  
Association Studies ◽  
High Dimensional ◽  
Selection Strategy ◽  
Methylation Data ◽  
Selection Probability ◽  
Cancer Data ◽  
Cpg Sites

In genetic association studies, regularization methods are often used due to their computational efficiency for analysis of high-dimensional genomic data. DNA methylation data generated from Infinium HumanMethylation450 BeadChip Kit have a group structure where an individual gene consists of multiple Cytosine–phosphate–Guanine (CpG) sites. Consequently, group-based regularization can precisely detect outcome-related CpG sites. Representative examples are sparse group lasso (SGL) and network-based regularization. The former is powerful when most of the CpG sites within the same gene are associated with a phenotype outcome. In contrast, the latter is preferred when only a few of the CpG sites within the same gene are related to the outcome. In this paper, we propose new variable selection strategy based on a selection probability that measures selection frequency of individual variables selected by both SGL and network-based regularization. In extensive simulation study, we demonstrated that the proposed strategy can show relatively outstanding selection performance under any situation, compared with both SGL and network-based regularization. Also, we applied the proposed strategy to identify differentially methylated CpG sites and their corresponding genes from ovarian cancer data.

scholarly journals Functional Characterization of a Testis-Specific DNA Binding Activity at the H19/Igf2 Imprinting Control Region

2003 ◽  
Vol 23 (22) ◽  
pp. 8345-8351 ◽  
Author(s):  
Aaron B. Bowman ◽  
John M. Levorse ◽  
Robert S. Ingram ◽  
Shirley M. Tilghman
Keyword(s):  
Dna Methylation ◽  
Dna Binding ◽  
Control Region ◽  
Binding Sites ◽  
Germ Line ◽  
Binding Activity ◽  
Wild Type ◽  
Dna Binding Activity ◽  
Epigenetic State ◽  
Imprinting Control Region

ABSTRACT The DNA methylation state of the H19/Igf2 imprinting control region (ICR) is differentially set during gametogenesis. To identify factors responsible for the paternally specific DNA methylation of the ICR, germ line and somatic extracts were screened for proteins that bind to the ICR in a germ line-specific manner. A specific DNA binding activity that was restricted to the male germ line and enriched in neonatal testis was identified. Its three binding sites within the ICR are very similar to the consensus sequence for nuclear receptor extended half sites. To determine if these binding sites are required for establishment of the paternal epigenetic state, a mouse strain in which the three sites were mutated was generated. The mutated ICR was able to establish a male-specific epigenetic state in sperm that was indistinguishable from that established by the wild-type ICR, indicating that these sequences are either redundant or have no function. An analysis of the methylated state of the mutant ICR in the soma revealed no differences from the wild-type ICR but did uncover in both mutant and wild-type chromosomes a significant relaxation in the stringency of the methylated state of the paternal allele and the unmethylated state of the maternal allele in neonatal and adult tissues.

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