scholarly journals Tissue- and ethnicity-independent hypervariable DNA methylation states show evidence of establishment in the early human embryo

2021 ◽  
Author(s):  
Maria Derakhshan ◽  
Noah J. Kessler ◽  
Miho Ishida ◽  
Charalambos Demetriou ◽  
Nicolas Brucato ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Monozygotic Twins ◽  
Early Embryo ◽  
Methylation Data ◽  
Cell Heterogeneity ◽  
Show Evidence ◽  
Health And Disease ◽  
Parent Of Origin ◽  
Heterogeneity Effects ◽  
Early Human

We analysed DNA methylation data from 30 datasets comprising 3,474 individuals, 19 tissues and 8 ethnicities at CpGs covered by the Illumina450K array. We identified 4,143 hypervariable CpGs ('hvCpGs') with methylation in the top 5% most variable sites across multiple tissues and ethnicities. hvCpG methylation was influenced but not determined by genetic variation, and was not linked to probe reliability, epigenetic drift, age, sex or cell heterogeneity effects. hvCpG methylation tended to covary across tissues derived from different germ-layers and hvCpGs were enriched for associations with periconceptional environment, proximity to ERV1 and ERVK retrovirus elements and parent-of-origin-specific methylation. They also showed distinctive methylation signatures in monozygotic twins. Together, these properties position hvCpGs as strong candidates for studying how stochastic and/or environmentally influenced DNA methylation states which are established in the early embryo and maintained stably thereafter can influence life-long health and disease.

scholarly journals Environmentally sensitive hotspots in the methylome of the early human embryo

2019 ◽  
Author(s):  
Matt J. Silver ◽  
Ayden Saffari ◽  
Noah J. Kessler ◽  
Giriraj R. Chandak ◽  
Caroline H.D. Fall ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Natural Experiment ◽  
Bioinformatic Analysis ◽  
Early Embryo ◽  
Early Environment ◽  
Gene Environment ◽  
Environmentally Sensitive ◽  
Parent Of Origin ◽  
Early Human

ABSTRACTIn humans, DNA methylation marks inherited from sperm and egg are largely erased immediately following conception, prior to construction of the embryonic methylome. Exploiting a natural experiment of cyclical seasonal variation including changes in diet and nutritional status in rural Gambia, we replicated 125 loci with a common season-of-conception methylation signature in two independent child cohorts, providing evidence of environmental effects on DNA methylation in the early embryo that persist at least until mid-childhood. Bioinformatic analysis revealed that these loci were highly enriched for metastable epialleles, parent-of-origin specific methylation and regions hypomethylated in sperm, and for H3K9me3 and H3K27me3 histone marks in multiple tissues. They tended to co-locate with endogenous retroviral (ERV1, ERVK) elements. Identified loci were influenced but not determined by measured genetic variation, notably through gene-environment interactions. To the extent that early methylation changes impact gene expression, environmental sensitivity during early embryo genomic remethylation could thus constitute a sense-record-adapt mechanism linking early environment to later phenotype.

scholarly journals Revisiting genetic artifacts on DNA methylation microarrays exposes novel biological implications

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Benjamin Planterose Jiménez ◽  
Manfred Kayser ◽  
Athina Vidaki
Keyword(s):  
Dna Methylation ◽  
Paradigm Shift ◽  
Monozygotic Twins ◽  
R Package ◽  
Probe Design ◽  
Methylation Data ◽  
Health And Disease ◽  
Specific Regulation ◽  
Novel Strategy ◽  
Methylation Quantitative Trait Loci

Abstract Background Illumina DNA methylation microarrays enable epigenome-wide analysis vastly used for the discovery of novel DNA methylation variation in health and disease. However, the microarrays’ probe design cannot fully consider the vast human genetic diversity, leading to genetic artifacts. Distinguishing genuine from artifactual genetic influence is of particular relevance in the study of DNA methylation heritability and methylation quantitative trait loci. But despite its importance, current strategies to account for genetic artifacts are lagging due to a limited mechanistic understanding on how such artifacts operate. Results To address this, we develop and benchmark UMtools, an R-package containing novel methods for the quantification and qualification of genetic artifacts based on fluorescence intensity signals. With our approach, we model and validate known SNPs/indels on a genetically controlled dataset of monozygotic twins, and we estimate minor allele frequency from DNA methylation data and empirically detect variants not included in dbSNP. Moreover, we identify examples where genetic artifacts interact with each other or with imprinting, X-inactivation, or tissue-specific regulation. Finally, we propose a novel strategy based on co-methylation that can discern between genetic artifacts and genuine genomic influence. Conclusions We provide an atlas to navigate through the huge diversity of genetic artifacts encountered on DNA methylation microarrays. Overall, our study sets the ground for a paradigm shift in the study of the genetic component of epigenetic variation in DNA methylation microarrays.

Epigenetics, Nutrition, Disease and Drug Development

2019 ◽  
Vol 16 (4) ◽  
pp. 386-391 ◽  
Author(s):  
Kenneth Lundstrom
Keyword(s):  
Dna Methylation ◽  
Drug Discovery ◽  
Rna Interference ◽  
Nutritional Requirements ◽  
Signal Pathways ◽  
Disease Development ◽  
Epigenetic Mechanisms ◽  
Epigenetic Changes ◽  
Health And Disease ◽  
Novel Drug

Epigenetic mechanisms comprising of DNA methylation, histone modifications and gene silencing by RNA interference have been strongly linked to the development and progression of various diseases. These findings have triggered research on epigenetic functions and signal pathways as targets for novel drug discovery. Dietary intake has also presented significant influence on human health and disease development and nutritional modifications have proven important in prevention, but also the treatment of disease. Moreover, a strong link between nutrition and epigenetic changes has been established. Therefore, in attempts to develop novel safer and more efficacious drugs, both nutritional requirements and epigenetic mechanisms need to be addressed.

DNA methylation fingerprint of monozygotic twins and their singleton sibling with intellectual disability carrying a novel KDM5C mutation

2020 ◽  
Vol 63 (3) ◽  
pp. 103737
Author(s):  
João V.S. Guerra ◽  
José Oliveira-Santos ◽  
Danyllo F. Oliveira ◽  
Gabriela F. Leal ◽  
João Ricardo M. Oliveira ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Intellectual Disability ◽  
Monozygotic Twins

scholarly journals DNA Methylation Profiles of Tph1A and BDNF in Gut and Brain of L. Rhamnosus-Treated Zebrafish

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 142
Author(s):  
Mariella Cuomo ◽  
Luca Borrelli ◽  
Rosa Della Monica ◽  
Lorena Coretti ◽  
Giulia De Riso ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Molecular Mechanisms ◽  
The Past ◽  
Targeted Analysis ◽  
Lack Of Information ◽  
High Resolution Power ◽  
Resolution Level ◽  
Health And Disease ◽  
High Doses ◽  
The Brain

The bidirectional microbiota–gut–brain axis has raised increasing interest over the past years in the context of health and disease, but there is a lack of information on molecular mechanisms underlying this connection. We hypothesized that change in microbiota composition may affect brain epigenetics leading to long-lasting effects on specific brain gene regulation. To test this hypothesis, we used Zebrafish (Danio Rerio) as a model system. As previously shown, treatment with high doses of probiotics can modulate behavior in Zebrafish, causing significant changes in the expression of some brain-relevant genes, such as BDNF and Tph1A. Using an ultra-deep targeted analysis, we investigated the methylation state of the BDNF and Tph1A promoter region in the brain and gut of probiotic-treated and untreated Zebrafishes. Thanks to the high resolution power of our analysis, we evaluated cell-to-cell methylation differences. At this resolution level, we found slight DNA methylation changes in probiotic-treated samples, likely related to a subgroup of brain and gut cells, and that specific DNA methylation signatures significantly correlated with specific behavioral scores.

Epigenetic study of global gene methylation in PON1, XRCC1 and GSTs different genotypes in rural and urban pesticide exposed workers

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Amal Saad-Hussein ◽  
Mona Mohamed Taha
Keyword(s):  
Dna Methylation ◽  
Dietary Habits ◽  
Pesticide Exposure ◽  
Alu Elements ◽  
Adverse Health Effects ◽  
Rural And Urban ◽  
Environmental Determinants Of Health ◽  
Pcr Rflp ◽  
Exposed Workers ◽  
Health And Disease

AbstractBackgroundEpigenetic represents a study of occurred heritable gene expression changes without changing in the DNA sequence. It includes DNA methylation and miRNA expression that attract increasing attention as potential links between the genetic and environmental determinants of health and disease. Pesticide exposure is associated with adverse health effects and DNA methylation due to oxidative stress induced following its exposure. This study aimed to define the association of genetic polymorphisms of XRCC1, PON1, GSTP1 and GST genes with global genes DNA methylation in urban and rural occupationally pesticides exposed workers.MethodsThis study included 100 pesticides exposed workers; 50 rural sprayers (RE) and 50 urban researchers (UE). Controls included equal numbers. DNA methylation of global genes was evaluated by pyrosequencing assay. XRCC1, PON1 and GSTP1 genotyping were assessed by PCR–RFLP, and GST M1 and T1 were performed by PCR.ResultsThe results of this study revealed that most genotypes in XRCC1, PON1, GSTP1 and GST genes were associated with LINE-1 hypomethylation among UE group. However, heterozygote genotypes (Gln-Arg and Ile-Val) in XRCC1 and GSTP1 genes, respectively, were associated with LINE-1 hypermethylation among UE compared with other corresponding genotypes. Only GSTT1 polymorphism recorded a significant change in percent methylation of Alu elements among urban and rural groups.ConclusionUrbanization could play an additional risk for epigenetic changes associated with pesticide exposure, and that could be attributed to the quality of life including their dietary habits, working and living in closed areas, and their exposure to extra pollutions emitted from urbanization sources.

scholarly journals A Genome-Wide Integrative Association Study of DNA Methylation and Gene Expression Data and Later Life Cognitive Functioning in Monozygotic Twins

2020 ◽  
Vol 14 ◽  
Author(s):  
Mette Soerensen ◽  
Dominika Marzena Hozakowska-Roszkowska ◽  
Marianne Nygaard ◽  
Martin J. Larsen ◽  
Veit Schwämmle ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Cognitive Functioning ◽  
Association Study ◽  
Gene Expression Data ◽  
Monozygotic Twins ◽  
Later Life ◽  
Expression Data ◽  
Genome Wide ◽  
A Genome

scholarly journals EMeth: An EM algorithm for cell type decomposition based on DNA methylation data

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hanyu Zhang ◽  
Ruoyi Cai ◽  
James Dai ◽  
Wei Sun
Keyword(s):  
Dna Methylation ◽  
Tumor Cells ◽  
T Regulatory Cells ◽  
Simulated Data ◽  
Cell Types ◽  
Computational Method ◽  
Methylation Data ◽  
Cell Type ◽  
A Cell ◽  
Type Decomposition

AbstractWe introduce a new computational method named EMeth to estimate cell type proportions using DNA methylation data. EMeth is a reference-based method that requires cell type-specific DNA methylation data from relevant cell types. EMeth improves on the existing reference-based methods by detecting the CpGs whose DNA methylation are inconsistent with the deconvolution model and reducing their contributions to cell type decomposition. Another novel feature of EMeth is that it allows a cell type with known proportions but unknown reference and estimates its methylation. This is motivated by the case of studying methylation in tumor cells while bulk tumor samples include tumor cells as well as other cell types such as infiltrating immune cells, and tumor cell proportion can be estimated by copy number data. We demonstrate that EMeth delivers more accurate estimates of cell type proportions than several other methods using simulated data and in silico mixtures. Applications in cancer studies show that the proportions of T regulatory cells estimated by DNA methylation have expected associations with mutation load and survival time, while the estimates from gene expression miss such associations.

scholarly journals Evaluation of affinity-based genome-wide DNA methylation data: Effects of CpG density, amplification bias, and copy number variation

2010 ◽  
Vol 20 (12) ◽  
pp. 1719-1729 ◽  
Author(s):  
M. D. Robinson ◽  
C. Stirzaker ◽  
A. L. Statham ◽  
M. W. Coolen ◽  
J. Z. Song ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Copy Number Variation ◽  
Copy Number ◽  
Methylation Data ◽  
Amplification Bias ◽  
Genome Wide ◽  
Number Variation

scholarly journals Increased serotonin transporter gene (SERT) DNA methylation is associated with bullying victimization and blunted cortisol response to stress in childhood: a longitudinal study of discordant monozygotic twins

2012 ◽  
Vol 43 (9) ◽  
pp. 1813-1823 ◽  
Author(s):  
I. Ouellet-Morin ◽  
C. C. Y. Wong ◽  
A. Danese ◽  
C. M. Pariante ◽  
A. S. Papadopoulos ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Serotonin Transporter ◽  
Life Stress ◽  
Monozygotic Twins ◽  
Early Life Stress ◽  
Serotonin Transporter Gene ◽  
Bullying Victimization ◽  
Transporter Gene ◽  
Twin Design ◽  
Response To Stress

BackgroundChildhood adverse experiences are known to induce persistent changes in the hypothalamic–pituitary–adrenal (HPA) axis reactivity to stress. However, the mechanisms by which these experiences shape the neuroendocrine response to stress remain unclear.MethodWe tested whether bullying victimization influenced serotonin transporter gene (SERT) DNA methylation using a discordant monozygotic (MZ) twin design. A subsample of 28 MZ twin pairs discordant for bullying victimization, with data on cortisol and DNA methylation, were identified in the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative 1994–1995 cohort of families with twins.ResultsBullied twins had higher SERT DNA methylation at the age of 10 years compared with their non-bullied MZ co-twins. This group difference cannot be attributed to the children's genetic makeup or their shared familial environments because of the study design. Bullied twins also showed increasing methylation levels between the age of 5 years, prior to bullying victimization, and the age of 10 years whereas no such increase was detected in non-bullied twins across time. Moreover, children with higher SERT methylation levels had blunted cortisol responses to stress.ConclusionsOur study extends findings drawn from animal models, supports the hypothesis that early-life stress modifies DNA methylation at a specific cytosine–phosphate–guanine (CpG) site in the SERT promoter and HPA functioning and suggests that these two systems may be functionally associated.

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