Weighted Gene Coregulation Network Analysis of Promoter DNA Methylation on All-Cause Mortality in Old-Aged Birth Cohorts Finds Modules of High-Risk Associated Biomarkers

Abstract Overall or all-cause mortality is a key measure of health in a population. Multiple epigenome-wide association studies have been conducted on all-cause mortality with limited significant findings and low replication. To elucidate the coregulated DNA methylation patterns associated with all-cause mortality, we conducted a weighted DNA methylation coregulation network analysis on whole-blood samples of 1,425 older individuals from the Lothian Birth Cohorts of 1921 and 1936. Our network-based analysis defined coregulated DNA methylation patterns in gene promoters into clusters or modules whose correlation with all-cause mortality was assessed by survival analysis. We found two significant modules or gene clusters associated with all-cause mortality in LBC1921 based on their eigengenes; one negatively correlated (p = 8.14E-03, 698 genes) and one positively correlated (p = 4.26E-02, 1,431 genes) with the risk of death. The two modules were replicated in LBC1936 with the same directions of correlation (p = 6.35E-02 and p = 3.64E-02, respectively). Furthermore, the modules revealed 32 genes associated with all-cause mortality (FDR < 0.05) linked to various diseases, including cancer and diabetes. Additionally, we performed pathway analysis and found 22 pathways (FDR < 0.05), including a pathway for taste transduction, which has been shown to be associated with poor prognosis in acutely hospitalized patients, and several pathways were linked to different types of cancer. The results from our network analysis show that DNA methylation of multiple genes could have been coregulated in an association with the overall risk of death. The identified epigenetic markers might help with our understanding of the molecular basis of all-cause mortality and general health.

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Abstract 40: Disturbed Flow Alters Genomewide DNA Methylation Patterns, Regulating Endothelial Gene Expression and Atherosclerosis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.34.suppl_1.40 ◽

2014 ◽

Vol 34 (suppl_1) ◽

Author(s):

Jessilyn Dunn ◽

Haiwei Qiu ◽

Soyeon Kim ◽

Daudi Jjingo ◽

Ryan Hoffman ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Dna Methyltransferase ◽

Methylation Status ◽

Western Diet ◽

Dependent Manner ◽

Gene Promoters ◽

Genome Wide ◽

Methylation Patterns ◽

Endothelial Gene Expression

Atherosclerosis preferentially occurs in arterial regions of disturbed blood flow (d-flow), which alters gene expression, endothelial function, and atherosclerosis. Here, we show that d-flow regulates genome-wide DNA methylation patterns in a DNA methyltransferase (DNMT)-dependent manner. We found that d-flow induced expression of DNMT1, but not DNMT3a or DNMT3b, in mouse arterial endothelium in vivo and in cultured endothelial cells by oscillatory shear (OS) compared to unidirectional laminar shear in vitro. The DNMT inhibitor 5-Aza-2’deoxycytidine (5Aza) or DNMT1 siRNA significantly reduced OS-induced endothelial inflammation. Moreover, 5Aza reduced lesion formation in two atherosclerosis models using ApoE-/- mice (western diet for 3 months and the partial carotid ligation model with western diet for 3 weeks). To identify the 5Aza mechanisms, we conducted two genome-wide studies: reduced representation bisulfite sequencing (RRBS) and transcript microarray using endothelial-enriched gDNA and RNA, respectively, obtained from the partially-ligated left common carotid artery (LCA exposed to d-flow) and the right contralateral control (RCA exposed to s-flow) of mice treated with 5Aza or vehicle. D-flow induced DNA hypermethylation in 421 gene promoters, which was significantly prevented by 5Aza in 335 genes. Systems biological analyses using the RRBS and the transcriptome data revealed 11 mechanosensitive genes whose promoters were hypermethylated by d-flow but rescued by 5Aza treatment. Of those, five genes contain hypermethylated cAMP-response-elements in their promoters, including the transcription factors HoxA5 and Klf3. Their methylation status could serve as a mechanosensitive master switch in endothelial gene expression. Our results demonstrate that d-flow controls epigenomic DNA methylation patterns in a DNMT-dependent manner, which in turn alters endothelial gene expression and induces atherosclerosis.

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DNA methylation-based sex classifier to predict sex and identify sex chromosome aneuploidy

10.1101/2020.10.19.345090 ◽

2020 ◽

Author(s):

Yucheng Wang ◽

Eilis Hannon ◽

Olivia A Grant ◽

Tyler J Gorrie-Stone ◽

Meena Kumari ◽

...

Keyword(s):

Dna Methylation ◽

Sex Chromosome ◽

Klinefelter Syndrome ◽

Association Studies ◽

Gene Expression Omnibus ◽

Sex Chromosome Aneuploidy ◽

Chromosome Aneuploidy ◽

Wide Range ◽

Almost All ◽

Methylation Patterns

AbstractSex is an important covariate of epigenome-wide association studies due to its strong influence on DNA methylation patterns across numerous genomic positions. Nevertheless, many samples on the Gene Expression Omnibus (GEO) frequently lack a sex annotation or are incorrectly labelled. Considering the influence that sex imposes on DNA methylation patterns, it is necessary to ensure that methods for filtering poor samples and checking of sex assignment are accurate and widely applicable. In this paper, we presented a novel method to predict sex using only DNA methylation density signals, which can be readily applied to almost all DNA methylation datasets of different formats (raw IDATs or text files with only density signals) uploaded to GEO. We identified 4345 significantly (p < 0.01) sex-associated CpG sites present on both 450K and EPIC arrays, and constructed a sex classifier based on the two first components of PCAs from the two sex chromosomes. The proposed method is constructed using whole blood samples and exhibits good performance across a wide range of tissues. We further demonstrated that our method can be used to identify samples with sex chromosome aneuploidy, this function is validated by five Turner syndrome cases and one Klinefelter syndrome case. The proposed method has been integrated into the wateRmelon Bioconductor package.

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Ultradeep Bisulfite Sequencing Analysis of DNA Methylation Patterns in Multiple Gene Promoters by 454 Sequencing

Cancer Research ◽

10.1158/0008-5472.can-07-1016 ◽

2007 ◽

Vol 67 (18) ◽

pp. 8511-8518 ◽

Cited By ~ 196

Author(s):

Kristen H. Taylor ◽

Robin S. Kramer ◽

J. Wade Davis ◽

Juyuan Guo ◽

Deiter J. Duff ◽

...

Keyword(s):

Dna Methylation ◽

Bisulfite Sequencing ◽

454 Sequencing ◽

Sequencing Analysis ◽

Gene Promoters ◽

Multiple Gene ◽

Methylation Patterns ◽

Bisulfite Sequencing Analysis

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Joint associations of accelerometer-measured physical activity and sedentary time with all-cause mortality: a harmonised meta-analysis in more than 44 000 middle-aged and older individuals

British Journal of Sports Medicine ◽

10.1136/bjsports-2020-103270 ◽

2020 ◽

Vol 54 (24) ◽

pp. 1499-1506

Author(s):

Ulf Ekelund ◽

Jakob Tarp ◽

Morten W Fagerland ◽

Jostein Steene Johannessen ◽

Bjørge H Hansen ◽

...

Keyword(s):

Physical Activity ◽

Proportional Hazards ◽

Sedentary Time ◽

Meta Analysis ◽

Cox Proportional Hazards ◽

Older Individuals ◽

Risk Of Death ◽

All Cause Mortality ◽

Reported Data ◽

Joint Associations

ObjectivesTo examine the joint associations of accelerometer-measured physical activity and sedentary time with all-cause mortality.MethodsWe conducted a harmonised meta-analysis including nine prospective cohort studies from four countries. 44 370 men and women were followed for 4.0 to 14.5 years during which 3451 participants died (7.8% mortality rate). Associations between different combinations of moderate-to-vigorous intensity physical activity (MVPA) and sedentary time were analysed at study level using Cox proportional hazards regression analysis and summarised using random effects meta-analysis.ResultsAcross cohorts, the average time spent sedentary ranged from 8.5 hours/day to 10.5 hours/day and 8 min/day to 35 min/day for MVPA. Compared with the referent group (highest physical activity/lowest sedentary time), the risk of death increased with lower levels of MVPA and greater amounts of sedentary time. Among those in the highest third of MVPA, the risk of death was not statistically different from the referent for those in the middle (16%; 95% CI 0.87% to 1.54%) and highest (40%; 95% CI 0.87% to 2.26%) thirds of sedentary time. Those in the lowest third of MVPA had a greater risk of death in all combinations with sedentary time; 65% (95% CI 1.25% to 2.19%), 65% (95% CI 1.24% to 2.21%) and 263% (95% CI 1.93% to 3.57%), respectively.ConclusionHigher sedentary time is associated with higher mortality in less active individuals when measured by accelerometry. About 30–40 min of MVPA per day attenuate the association between sedentary time and risk of death, which is lower than previous estimates from self-reported data.

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DNA methylation-based sex classifier to predict sex and identify sex chromosome aneuploidy

BMC Genomics ◽

10.1186/s12864-021-07675-2 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Yucheng Wang ◽

Eilis Hannon ◽

Olivia A. Grant ◽

Tyler J. Gorrie-Stone ◽

Meena Kumari ◽

...

Keyword(s):

Dna Methylation ◽

Sex Chromosome ◽

Klinefelter Syndrome ◽

Association Studies ◽

Gene Expression Omnibus ◽

Sex Chromosome Aneuploidy ◽

Chromosome Aneuploidy ◽

Wide Range ◽

Almost All ◽

Methylation Patterns

Abstract Background Sex is an important covariate of epigenome-wide association studies due to its strong influence on DNA methylation patterns across numerous genomic positions. Nevertheless, many samples on the Gene Expression Omnibus (GEO) frequently lack a sex annotation or are incorrectly labelled. Considering the influence that sex imposes on DNA methylation patterns, it is necessary to ensure that methods for filtering poor samples and checking of sex assignment are accurate and widely applicable. Results Here we presented a novel method to predict sex using only DNA methylation beta values, which can be readily applied to almost all DNA methylation datasets of different formats (raw IDATs or text files with only signal intensities) uploaded to GEO. We identified 4345 significantly (p<0.01) sex-associated CpG sites present on both 450K and EPIC arrays, and constructed a sex classifier based on the two first principal components of the DNA methylation data of sex-associated probes mapped on sex chromosomes. The proposed method is constructed using whole blood samples and exhibits good performance across a wide range of tissues. We further demonstrated that our method can be used to identify samples with sex chromosome aneuploidy, this function is validated by five Turner syndrome cases and one Klinefelter syndrome case. Conclusions This proposed sex classifier not only can be used for sex predictions but also applied to identify samples with sex chromosome aneuploidy, and it is freely and easily accessible by calling the ‘estimateSex’ function from the newest wateRmelon Bioconductor package (https://github.com/schalkwyk/wateRmelon).

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DNA methylation patterns of RAR ‐β2 and RASSF1A gene promoters in FNAB samples from Greek population with benign or malignant breast lesions

Diagnostic Cytopathology ◽

10.1002/dc.24513 ◽

2020 ◽

Vol 49 (1) ◽

pp. 153-164

Author(s):

Niki Kougioumtsidou ◽

Eleftherios Vavoulidis ◽

Maria Nasioutziki ◽

Marianthi Symeonidou ◽

Georgios Chrysostomos Pratilas ◽

...

Keyword(s):

Dna Methylation ◽

Greek Population ◽

Breast Lesions ◽

Gene Promoters ◽

Rassf1a Gene ◽

Malignant Breast ◽

Methylation Patterns

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An investigation into DNA methylation patterns associated with risk preference in older individuals

Epigenetics ◽

10.1080/15592294.2021.1992910 ◽

2021 ◽

Author(s):

Laura J. Smyth ◽

Sharon M. Cruise ◽

Jianjun Tang ◽

Ian Young ◽

Bernadette McGuinness ◽

...

Keyword(s):

Dna Methylation ◽

Risk Preference ◽

Older Individuals ◽

Methylation Patterns

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Epigenetic modifications and their role in the development and disease progression of type 2 diabetes

International Journal of Community Medicine and Public Health ◽

10.18203/2394-6040.ijcmph20210250 ◽

2021 ◽

Vol 8 (2) ◽

pp. 948

Author(s):

Abhijeet Roy

Keyword(s):

Type 2 Diabetes ◽

Dna Methylation ◽

Epigenetic Regulation ◽

Association Studies ◽

Normal Subjects ◽

Genome Wide Association Studies ◽

Non Coding Rna ◽

Genome Wide ◽

Methylation Patterns

Type 2 Diabetes is one of the major public health issues and a complex metabolic disorder strongly associated with genetic predisposition influenced by environmental factors and epigenetic regulation. This review paper illustrated the role of epigenetics in the pathogenesis, progression, and detection of Type 2 Diabetes. A review study was performed for the articles published in English from 2000-2019 using Pub Med, and Google Scholar databases. Main underlining mechanisms of Type 2 Diabetes were identified; insulin resistance in the peripheral tissue, and disintegrate insulin secretion. Genome Wide Association Studies suggested that epigenetic regulation such as DNA methylation, Histone modification, Non-coding RNA, microRNA is strongly related with the development of Type 2 Diabetes. Altered DNA methylation patterns in pancreatic islets, skeletal muscle, adipose tissue, from diabetic subjects compare to normal subjects was also found. Other risk factors like; obesity, age, gender, impaired glucose tolerance, periconception and intrauterine environment may also have been linked with the possibilities of epigenetic changes. Epigenetics plays a crucial role by modifying the gene expression and establish a relationship between the environment and genetic factors. Understanding the epigenetic mechanisms contributing to the development of Type 2 Diabetes is still limited.

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DNA Methylation Is Responsive to the Environment and Regulates the Expression of Biosynthetic Gene Clusters, Metabolite Production, and Virulence in Fusarium graminearum

Frontiers in Fungal Biology ◽

10.3389/ffunb.2020.614633 ◽

2021 ◽

Vol 1 ◽

Author(s):

Christopher Bonner ◽

Amanda Sproule ◽

Owen Rowland ◽

David Overy ◽

Rajagopal Subramaniam

Keyword(s):

Dna Methylation ◽

Fusarium Graminearum ◽

External Environment ◽

Gene Clusters ◽

Dna Methyltransferases ◽

Biosynthetic Gene ◽

Biosynthetic Gene Clusters ◽

Mutant Strains ◽

Average Methylation ◽

Methylation Patterns

Histone modifications play a significant role in the regulation of biosynthetic gene clusters (BGCs) in the phytopathogen Fusarium graminearum, by contrast, epigenetic regulation by DNA methyltransferases (DNMTs) is less documented. In this study, we characterized two DNMTs (FgDIM-2 and FgRID) in F. graminearum, with homologies to “Deficient in methylation” (DIM-2) and “Repeat-induced point (RIP) deficient” (RID) from Neurospora. The loss of DNMTs resulted in not only a decrease in average methylation density in the nutrient-poor, compared to nutrient-rich conditions, but also differences in the genes expressed between the WT and the DNMT mutant strains, implicating the external environment as an important trigger in altering DNA methylation patterns. Consequently, we observed significant changes in the regulation of multiple BGCs and alterations in the pathogenicity of the fungus.

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Maternal exposure to cigarette smoking induces immediate and durable changes in placental DNA methylation affecting enhancer and imprinting control regions

10.1101/852186 ◽

2019 ◽

Cited By ~ 1

Author(s):

Sophie Rousseaux ◽

Emie Seyve ◽

Florent Chuffart ◽

Ekaterina Bourova-Flin ◽

Meriem Benmerad ◽

...

Keyword(s):

Dna Methylation ◽

Cigarette Smoking ◽

Smoking Status ◽

Gene Clusters ◽

Tobacco Exposure ◽

Smoking During Pregnancy ◽

Former Smokers ◽

Genomic Regions ◽

Methylation Patterns ◽

Control Regions

AbstractObjectiveExposure to cigarette smoking during pregnancy has been robustly associated with cord blood DNA methylation. However, little is known about such effects on the placenta; in particular, whether cigarette smoking before pregnancy could also induce epigenetic alterations in the placenta of former smokers is unknown.Design and resultsPlacental DNA methylation levels were measured in 568 women and compared among non-smokers and women either smoking during their pregnancy or who had ceased smoking before pregnancy. An Epigenome Wide Association Study identified 344 Differentially Methylated Regions (DMRs) significantly associated with maternal smoking status. Among these 344 DMRs, 262 showed “reversible” alterations of DNA methylation, only present in the placenta of current smokers, whereas 44 were also found altered in former smokers, whose placenta had not been exposed directly to cigarette smoking. This observation was further supported by a significant demethylation of LINE-1 sequences in the placentas of both current (−0.43 (−0.83 to −0.02)) and former smokers (−0.55 (−1.02 to −0.08)) compared to nonsmokers. A comparative analysis of the epigenome landscape based on the ENCODE placenta data demonstrated an enrichment of all 344 DMRs in enhancers histone marks. Additionally, smoking-associated DMRs were found near and/or overlapping with 13 imprinting gene clusters encompassing 18 imprinted genes.ConclusionsDNA methylation patterns alterations were found in 344 genomic regions in the placenta of women smoking during their pregnancy, including 44 DMRs and LINE-1 elements, where methylation changes persisted in former smokers, supporting the hypothesis of an “epigenetic memory” of exposure to cigarette smoking before pregnancy. Enhancers regions, including imprinting control regions were also particularly affected by placenta methylation changes associated to smoking, suggesting a biological basis for the sensitivity of these regions to tobacco exposure and mechanisms by which fetal development could be impacted.

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