scholarly journals Lifetime Ultraviolet Radiation Exposure and Dna Methylation In Blood Leukocytes: The Norwegian Women And Cancer Study

2019 ◽  
Author(s):  
Christian M Page ◽  
Vera Djordjilović ◽  
Therese H Nøst ◽  
Reza Ghiasvand ◽  
Torkjel M Sandanger ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Ultraviolet Radiation ◽  
Molecular Mechanisms ◽  
Indoor Tanning ◽  
The Other ◽  
Data Set ◽  
Global Methylation ◽  
Cpg Sites ◽  
Genome Wide ◽  
A Genome

Abstract Background Ultraviolet radiation (UVR) exposure is a leading cause of skin cancers and an ubiquitous environmental exposure. However, the molecular mechanisms relating UVR exposure to melanoma is not fully understood. We aimed to investigate if lifetime UVR exposure influences DNA methylation, and if individual CpG sites could be robustly associated with UVR exposures.Methods We assessed DNA methylation in whole blood in three data sets (N = 183, 191, and 125) from the Norwegian Women and Cancer cohort, using Illumina methylation platforms (450k & EPIC). We studied genome-wide DNA methylation, targeted analyses of CpG sites indicated in the literature, global methylation (average over all CpGs and imputation of LINE-1 specific CpGs), and accelerated aging. Lifetime history of UVR exposure (residential ambient UVR, sunburns, sunbathing vacations and indoor tanning) was collected by questionnaires. Cumulative UVR exposure was calculated by adding sunbathing vacations and indoor tanning. We used one data set for discovery and the other two for replication. Results One CpG site showed a genome-wide significant association between cumulative UVR exposure and DNA methylation (cg01884057) (pnominal=3.96e-08), but was not replicated in any of the two replication sets (pnominal≥0.42). Four CpG sites (cg05860019, cg00033666, cg18984282, cg25792367) showed suggestive associations with the other UVR exposures. Conclusion We performed extensive analyses of the association between long-term UVR exposure and DNA methylation in lymphocytes. There was no indication of a robust effect of past UVR exposure on DNA methylation, and our results do not suggest mediation of UVR effects on melanoma risk by DNA methylation.

scholarly journals Stable DNMT3L overexpression in SH-SY5Y neurons recreates a facet of the genome-wide Down syndrome DNA methylation signature

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Benjamin I. Laufer ◽  
J. Antonio Gomez ◽  
Julia M. Jianu ◽  
Janine M. LaSalle
Keyword(s):  
Dna Methylation ◽  
Down Syndrome ◽  
Neuronal Differentiation ◽  
Molecular Mechanisms ◽  
Cpg Island ◽  
Differential Methylation ◽  
Chromosome 21 ◽  
Pairwise Comparisons ◽  
Genome Wide ◽  
A Genome

Abstract Background Down syndrome (DS) is characterized by a genome-wide profile of differential DNA methylation that is skewed towards hypermethylation in most tissues, including brain, and includes pan-tissue differential methylation. The molecular mechanisms involve the overexpression of genes related to DNA methylation on chromosome 21. Here, we stably overexpressed the chromosome 21 gene DNA methyltransferase 3L (DNMT3L) in the human SH-SY5Y neuroblastoma cell line and assayed DNA methylation at over 26 million CpGs by whole genome bisulfite sequencing (WGBS) at three different developmental phases (undifferentiated, differentiating, and differentiated). Results DNMT3L overexpression resulted in global CpG and CpG island hypermethylation as well as thousands of differentially methylated regions (DMRs). The DNMT3L DMRs were skewed towards hypermethylation and mapped to genes involved in neurodevelopment, cellular signaling, and gene regulation. Consensus DNMT3L DMRs showed that cell lines clustered by genotype and then differentiation phase, demonstrating sets of common genes affected across neuronal differentiation. The hypermethylated DNMT3L DMRs from all pairwise comparisons were enriched for regions of bivalent chromatin marked by H3K4me3 as well as differentially methylated sites from previous DS studies of diverse tissues. In contrast, the hypomethylated DNMT3L DMRs from all pairwise comparisons displayed a tissue-specific profile enriched for regions of heterochromatin marked by H3K9me3 during embryonic development. Conclusions Taken together, these results support a mechanism whereby regions of bivalent chromatin that lose H3K4me3 during neuronal differentiation are targeted by excess DNMT3L and become hypermethylated. Overall, these findings demonstrate that DNMT3L overexpression during neurodevelopment recreates a facet of the genome-wide DS DNA methylation signature by targeting known genes and gene clusters that display pan-tissue differential methylation in DS.

scholarly journals Stable DNMT3L Overexpression in SH-SY5Y Neurons Recreates a Facet of the Genome-Wide Down Syndrome DNA Methylation Signature

2020 ◽  
Author(s):  
Benjamin I. Laufer ◽  
J. Antonio Gomez ◽  
Julia M. Jianu ◽  
Janine M. LaSalle
Keyword(s):  
Dna Methylation ◽  
Down Syndrome ◽  
Dna Methyltransferase ◽  
Molecular Mechanisms ◽  
Cpg Island ◽  
Neuroblastoma Cell ◽  
Chromosome 21 ◽  
Pairwise Comparisons ◽  
Genome Wide ◽  
A Genome

AbstractDown syndrome (DS) is characterized by a genome-wide profile of differential DNA methylation that is skewed towards hypermethylation in most tissues, including brain. The molecular mechanisms involve the overexpression of genes related to DNA methylation on chromosome 21. Here, we stably overexpressed the chromosome 21 gene DNA methyltransferase 3L (DNMT3L) in the human SH-SY5Y neuroblastoma cell line and assayed DNA methylation at over 26 million CpGs by whole genome bisulfite sequencing at three different developmental phases (undifferentiated, differentiating, and differentiated). DNMT3L overexpression resulted in global CpG and CpG island hypermethylation as well as thousands of differentially methylated regions (DMRs). The DNMT3L DMRs were skewed towards hypermethylation and mapped to genes involved in neurodevelopment, cellular signaling, and gene regulation. Merging the DMRs into a consensus profile where the cell lines clustered by genotype and then phase demonstrated that different regions of common genes are affected. The hypermethylated DMRs from all pairwise comparisons were enriched for regions of bivalent chromatin marked by H3K4me3 as well as differentially methylated CpGs from previous DS studies of diverse tissues. In contrast, the hypomethylated DMRs from all pairwise comparisons displayed a tissue-specific profile enriched for regions of heterochromatin marked by H3K9me3 during embryonic development. Taken together, we propose a mechanism whereby regions of bivalent chromatin that lose H3K4me3 during development are targeted by excess DNMT3L and become hypermethylated, while excess DNMT3L also evicts DNMT3A from heterochromatin, resulting in hypomethylation. Overall, these findings demonstrate that DNMT3L overexpression during neurodevelopment recreates a facet of the DS DNA methylation signature.

Genome-wide DNA methylation analysis reveals a prognostic classifier for non-metastatic colorectal cancer (ProMCol classifier)

Gut ◽  
2017 ◽  
Vol 68 (1) ◽  
pp. 101-110 ◽  
Author(s):  
Melanie Gündert ◽  
Dominic Edelmann ◽  
Axel Benner ◽  
Lina Jansen ◽  
Min Jia ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
Validation Cohort ◽  
Cox Model ◽  
Brier Score ◽  
P Value ◽  
Clinical Variables ◽  
Cpg Sites ◽  
Genome Wide ◽  
A Genome

ObjectivePathological staging used for the prediction of patient survival in colorectal cancer (CRC) provides only limited information.DesignHere, a genome-wide study of DNA methylation was conducted for two cohorts of patients with non-metastatic CRC (screening cohort (n=572) and validation cohort (n=274)). A variable screening for prognostic CpG sites was performed in the screening cohort using marginal testing based on a Cox model and subsequent adjustment of the p-values via independent hypothesis weighting using the methylation difference between 34 pairs of tumour and normal mucosa tissue as auxiliary covariate. From the 1000 CpG sites with the smallest adjusted p-value, 20 CpG sites with the smallest Brier score for overall survival (OS) were selected. Applying principal component analysis, we derived a prognostic methylation-based classifier for patients with non-metastatic CRC (ProMCol classifier).ResultsThis classifier was associated with OS in the screening (HR 0.51, 95% CI 0.41 to 0.63, p=6.2E−10) and the validation cohort (HR 0.61, 95% CI 0.45 to 0.82, p=0.001). The independent validation of the ProMCol classifier revealed a reduction of the prediction error for 3-year OS from 0.127, calculated only with standard clinical variables, to 0.120 combining the clinical variables with the classifier and for 4-year OS from 0.153 to 0.140. All results were confirmed for disease-specific survival.ConclusionThe ProMCol classifier could improve the prognostic accuracy for patients with non-metastatic CRC.

Genome-wide DNA methylation pattern in systemic sclerosis microvascular endothelial cells: Identification of epigenetically affected key genes and pathways

2021 ◽  
pp. 239719832110337
Author(s):  
Shadia Nada ◽  
Bashar Kahaleh ◽  
Nezam Altorok
Keyword(s):  
Dna Methylation ◽  
Endothelial Cells ◽  
Systemic Sclerosis ◽  
Microvascular Endothelial Cells ◽  
Cpg Sites ◽  
Genome Wide ◽  
A Genome ◽  
Diffuse Cutaneous Systemic Sclerosis ◽  
Microvascular Endothelial ◽  
Hypermethylated Genes

Background: The etiology of systemic sclerosis is not clear, but there is evidence suggesting a critical role for epigenetic alterations in disease pathogenesis and clinical expression. We sought, in this study, to characterize the genome-wide DNA methylation signature in systemic sclerosis microvascular endothelial cells. Methods: We performed a genome-wide DNA methylation study in microvascular endothelial cells derived from seven diffuse cutaneous systemic sclerosis patients compared to seven age-, sex-, and ethnicity-matched healthy controls. We paired matched samples on Illumina HumanMethylation450 (three diffuse cutaneous systemic sclerosis microvascular endothelial cells and three controls), and reproduced the results in an independent set of matched patient and controls using Illumina Infinium MethylationEPIC (four diffuse cutaneous systemic sclerosis patients and four controls) to identify differentially methylated genes. Results: We identified 71,353 differentially methylated CpG sites in systemic sclerosis microvascular endothelial cells using Infinium MethylationEPIC microarray in the first group (0.081% of representative probes) and 33,170 CpG sites in the second group using HumanMethylation450 microarray (0.073% of representative probes) in diffuse cutaneous systemic sclerosis microvascular endothelial cells. Among the two groups of subjects, we identified differential methylation of 2455 CpG sites, representing 1301 genes. Most of the differentially methylated CpG sites were hypermethylated (1625 CpG), corresponding to 910 genes. Common hypermethylated genes in systemic sclerosis microvascular endothelial cells include NOS1, DNMT3A, DNMT3B, HDAC4, and ANGPT2. We also identified hypomethylation of IL17RA, CTNNA3, ICAM2, and SDK1 in systemic sclerosis microvascular endothelial cells. Furthermore, we demonstrate significant inverse correlation between DNA methylation status and gene expression in the majority of genes evaluated. Gene ontology analysis of hypermethylated genes demonstrated enrichment of genes involved in angiogenesis ( p = 0.0006). Pathway analysis of hypomethylated genes includes genes involved in vascular smooth muscle contraction ( p = 0.014) and adherens junctions ( p = 0.013). Conclusion: Our data suggest the presence of significant genome-wide DNA methylation aberrancies in systemic sclerosis microvascular endothelial cells, and identify novel affected genes and pathways in systemic sclerosis microvascular endothelial cells.

scholarly journals Epigenetic mechanisms in pulmonary arterial hypertension: the need for global perspectives

2016 ◽  
Vol 25 (140) ◽  
pp. 135-140 ◽  
Author(s):  
Prakash Chelladurai ◽  
Werner Seeger ◽  
Soni Savai Pullamsetti
Keyword(s):  
Dna Methylation ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Epigenetic Mechanisms ◽  
Aberrant Expression ◽  
Genome Wide ◽  
A Genome ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a severe and progressive disease, characterised by high pulmonary artery pressure that usually culminates in right heart failure. Recent findings of alterations in the DNA methylation state of superoxide dismutase 2 and granulysin gene loci; histone H1 levels; aberrant expression levels of histone deacetylases and bromodomain-containing protein 4; and dysregulated microRNA networks together suggest the involvement of epigenetics in PAH pathogenesis. Thus, PAH pathogenesis evidently involves the interplay of a predisposed genetic background, epigenetic state and injurious events. Profiling the genome-wide alterations in the epigenetic mechanisms, such as DNA methylation or histone modification pattern in PAH vascular cells, may explain the great variability in susceptibility and disease severity that is frequently associated with pronounced remodelling and worse clinical outcome. Moreover, the influence of genetic predisposition and the acquisition of epigenetic alterations in response to environmental cues in PAH progression and establishment has largely been unexplored on a genome-wide scale. In order to gain insights into the molecular mechanisms leading to the development of PAH and to design novel therapeutic strategies, high-throughput approaches have to be adopted to facilitate systematic identification of the disease-specific networks using next-generation sequencing technologies, the application of these technologies in PAH has been relatively trivial to date.

scholarly journals The effect of age on DNA methylation in whole blood among Bangladeshi men and women

BMC Genomics ◽  
2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Rick J. Jansen ◽  
Lin Tong ◽  
Maria Argos ◽  
Farzana Jasmine ◽  
Muhammad Rakibuz-Zaman ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Whole Blood ◽  
Cpg Islands ◽  
Chronological Age ◽  
Cpg Sites ◽  
Age Related ◽  
Genome Wide ◽  
A Genome ◽  
Effect Of Age ◽  
Age Related Changes

Abstract Background It is well-known that methylation changes occur as humans age, however, understanding how age-related changes in DNA methylation vary by sex is lacking. In this study, we characterize the effect of age on DNA methylation in a sex-specific manner and determine if these effects vary by genomic context. We used the Illumina HumanMethylation 450 K array and DNA derived from whole blood for 400 adult participants (189 males and 211 females) from Bangladesh to identify age-associated CpG sites and regions and characterize the location of these age-associated sites with respect to CpG islands (vs. shore, shelf, or open sea) and gene regions (vs. intergenic). We conducted a genome-wide search for age-associated CpG sites (among 423,604 sites) using a reference-free approach to adjust for cell type composition (the R package RefFreeEWAS) and performed an independent replication analysis of age-associated CpGs. Results The number of age-associated CpGs (p < 5 x 10− 8) were 986 among men and 3479 among women of which 2027(63.8%) and 572 (64.1%) replicated (using Bonferroni adjusted p < 1.2 × 10− 5). For both sexes, age-associated CpG sites were more likely to be hyper-methylated with increasing age (compared to hypo-methylated) and were enriched in CpG islands and promoter regions compared with other locations and all CpGs on the array. Although we observed strong correlation between chronological age and previously-developed epigenetic age models (r ≈ 0.8), among our top (based on lowest p-value) age-associated CpG sites only 12 for males and 44 for females are included in these prediction models, and the median chronological age compared to predicted age was 44 vs. 51.7 in males and 45 vs. 52.1 in females. Conclusions Our results describe genome-wide features of age-related changes in DNA methylation. The observed associations between age and methylation were generally consistent for both sexes, although the associations tended to be stronger among women. Our population may have unique age-related methylation changes that are not captured in the established methylation-based age prediction model we used, which was developed to be non-tissue-specific.

scholarly journals Ultraviolet radiation modulates DNA methylation in melanocytes

2021 ◽  
Author(s):  
Sarah Preston-Alp ◽  
Jaroslav Jelinek ◽  
Jean-Pierre Issa ◽  
M. Raza Zaidi
Keyword(s):  
Dna Methylation ◽  
Ultraviolet Radiation ◽  
Molecular Mechanisms ◽  
Long Term Effects ◽  
Induced Mutations ◽  
Cpg Sites ◽  
Intergenic Regions ◽  
Underlying Mechanisms

Ultraviolet radiation (UVR) is the principal causal factor for melanoma; albeit the underlying mechanisms remain unclear. While the mutagenic properties of UVR are irrefutable, the role of UVR-induced mutations in the initiation of melanoma is controversial which highlights the gap in our knowledge of the initial critical molecular mechanisms of UVR-induced melanomagenesis. To investigate the potential non-mutational mechanisms of UVR-induced melanomagenesis, we studied the role of UVR in modulating DNA methylation changes in melanocytes via next-generation sequencing-based methodologies. Here we show that UVR directly causes stable changes in the DNA methylome and transcriptome, one month after exposure. Genomic features associated with transcription were protected from 5mC alterations whereas CpG sites found in intergenic regions were more likely to be affected. Additionally, the long-term effects of UVR seem to perturb signaling pathways important for melanocyte biology. Interestingly, UVR-sensitive CpG sites were found to be prognostic of overall patient survival and highlighted a subset of CpG sites that may be relevant in melanomagenesis.

scholarly journals DNA Methylation at ATP11A cg11702988 Is a Biomarker of Lung Disease Severity in Cystic Fibrosis: A Longitudinal Study

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 441
Author(s):  
Fanny Pineau ◽  
Davide Caimmi ◽  
Sylvie Taviaux ◽  
Maurane Reveil ◽  
Laura Brosseau ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Dna Methylation ◽  
Clinical Trials ◽  
Lung Disease ◽  
Disease Severity ◽  
Genome Wide ◽  
A Genome ◽  
Lung Disease Severity ◽  
Epigenetic Biomarker

Cystic fibrosis (CF) is a chronic genetic disease that mainly affects the respiratory and gastrointestinal systems. No curative treatments are available, but the follow-up in specialized centers has greatly improved the patient life expectancy. Robust biomarkers are required to monitor the disease, guide treatments, stratify patients, and provide outcome measures in clinical trials. In the present study, we outline a strategy to select putative DNA methylation biomarkers of lung disease severity in cystic fibrosis patients. In the discovery step, we selected seven potential biomarkers using a genome-wide DNA methylation dataset that we generated in nasal epithelial samples from the MethylCF cohort. In the replication step, we assessed the same biomarkers using sputum cell samples from the MethylBiomark cohort. Of interest, DNA methylation at the cg11702988 site (ATP11A gene) positively correlated with lung function and BMI, and negatively correlated with lung disease severity, P. aeruginosa chronic infection, and the number of exacerbations. These results were replicated in prospective sputum samples collected at four time points within an 18-month period and longitudinally. To conclude, (i) we identified a DNA methylation biomarker that correlates with CF severity, (ii) we provided a method to easily assess this biomarker, and (iii) we carried out the first longitudinal analysis of DNA methylation in CF patients. This new epigenetic biomarker could be used to stratify CF patients in clinical trials.

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 Eyes of Africa: The Genetics of Blindness: Study Design and Methodology

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Olusola Olawoye ◽  
Chimdi Chuka-Okosa ◽  
Onoja Akpa ◽  
Tony Realini ◽  
Michael Hauser ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Case Control Study ◽  
African Ancestry ◽  
Collaborative Study ◽  
Data Set ◽  
Human Heredity ◽  
Genome Wide ◽  
A Genome ◽  
Multiplex Families ◽  
Control Study

Abstract Background This report describes the design and methodology of the “Eyes of Africa: The Genetics of Blindness,” a collaborative study funded through the Human Heredity and Health in Africa (H3Africa) program of the National Institute of Health. Methods This is a case control study that is collecting a large well phenotyped data set among glaucoma patients and controls for a genome wide association study. (GWAS). Multiplex families segregating Mendelian forms of early-onset glaucoma will also be collected for exome sequencing. Discussion A total of 4500 cases/controls have been recruited into the study at the end of the 3rd funded year of the study. All these participants have been appropriately phenotyped and blood samples have been received from these participants. Recent GWAS of POAG in African individuals demonstrated genome-wide significant association with the APBB2 locus which is an association that is unique to individuals of African ancestry. This study will add to the existing knowledge and understanding of POAG in the African population.

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