Transgenerational Self-Reconstruction of Disrupted Chromatin Organization After Exposure To An Environmental Stressor in Mice

Abstract Exposure to environmental stressors is known to increase disease susceptibility in unexposed descendants in the absence of detectable genetic mutations. The mechanisms mediating environmentally-induced transgenerational disease susceptibility are poorly understood. We showed that great-great-grandsons of female mice exposed to tributyltin (TBT) throughout pregnancy and lactation were predisposed to obesity due to altered chromatin organization that subsequently biased DNA methylation and gene expression. Here we analyzed DNA methylomes and transcriptomes from tissues of animals ancestrally exposed to TBT spanning generations, sexes, ontogeny, and cell differentiation state. We found that TBT elicited concerted alterations in the expression of “chromatin organization” genes and inferred that TBT-disrupted chromatin organization might be able to self-reconstruct transgenerationally. We also found that the location of “chromatin organization” and “metabolic” genes is biased similarly in mouse and human genomes, suggesting that exposure to environmental stressors in different species could elicit similar phenotypic effects via self-reconstruction of disrupted chromatin organization.

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Relationships between chromatin organization and DNA methylation in determining gene expression

Seminars in Cancer Biology ◽

10.1006/scbi.1999.0134 ◽

1999 ◽

Vol 9 (5) ◽

pp. 339-347 ◽

Cited By ~ 102

Author(s):

Peter L. Jones ◽

Alan P. Wolffe

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Chromatin Organization

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DNA methylation differences of the BPI promoter among pig breeds and the regulation of gene expression

RSC Advances ◽

10.1039/c7ra05549h ◽

2017 ◽

Vol 7 (76) ◽

pp. 48025-48030 ◽

Cited By ~ 1

Author(s):

HaiFei Wang ◽

Jiayun Wu ◽

Sen Wu ◽

ShengLong Wu ◽

WenBin Bao

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Promoter Methylation ◽

Disease Susceptibility ◽

Regulation Of Gene Expression ◽

Pig Breeds

TheBPIpromoter methylation is distinct between different pig breeds and potentially associated with its expression and disease susceptibility.

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An integrative approach to detect epigenetic mechanisms that putatively mediate the influence of lifestyle exposures on disease susceptibility

International Journal of Epidemiology ◽

10.1093/ije/dyz119 ◽

2019 ◽

Vol 48 (3) ◽

pp. 887-898 ◽

Cited By ~ 6

Author(s):

Tom G Richardson ◽

Rebecca C Richmond ◽

Teri-Louise North ◽

Gibran Hemani ◽

George Davey Smith ◽

...

Keyword(s):

Gene Expression ◽

Risk Factors ◽

Dna Methylation ◽

Complex Traits ◽

Disease Susceptibility ◽

Association Studies ◽

Integrative Approach ◽

Prenatal Smoking ◽

Genome Wide Association Studies ◽

Cpg Sites

Abstract Background There is mounting evidence that our environment and lifestyle has an impact on epigenetic regulatory mechanisms, such as DNA methylation. It has been suggested that these molecular processes may mediate the effect of risk factors on disease susceptibility, although evidence in this regard has been challenging to uncover. Using genetic variants as surrogate variables, we have used two-sample Mendelian randomization (2SMR) to investigate the potential implications of putative changes to DNA methylation levels on disease susceptibility. Methods To illustrate our approach, we identified 412 CpG sites where DNA methylation was associated with prenatal smoking. We then applied 2SMR to investigate potential downstream effects of these putative changes on 643 complex traits using findings from large-scale genome-wide association studies. To strengthen evidence of mediatory mechanisms, we used multiple-trait colocalization to assess whether DNA methylation, nearby gene expression and complex trait variation were all influenced by the same causal genetic variant. Results We identified 22 associations that survived multiple testing (P < 1.89 × 10–7). In-depth follow-up analyses of particular note suggested that the associations between DNA methylation at the ASPSCR1 and REST/POL2RB gene regions, both linked with reduced lung function, may be mediated by changes in gene expression. We validated associations between DNA methylation and traits using independent samples from different stages across the life course. Conclusion Our approach should prove valuable in prioritizing CpG sites that may mediate the effect of causal risk factors on disease. In-depth evaluations of findings are necessary to robustly disentangle causality from alternative explanations such as horizontal pleiotropy.

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Epigenetic, transcriptional and phenotypic responses in two generations of Daphnia magna exposed to the DNA methylation inhibitor 5-azacytidine

Environmental Epigenetics ◽

10.1093/eep/dvz016 ◽

2019 ◽

Vol 5 (3) ◽

Cited By ~ 7

Author(s):

Leif Christopher Lindeman ◽

Jens Thaulow ◽

You Song ◽

Jorke H Kamstra ◽

Li Xie ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Histone Modifications ◽

Environmental Stressors ◽

Global Dna Methylation ◽

Two Generations ◽

Methylation Inhibitor ◽

Dna Methylation Inhibitor ◽

Offspring Generation ◽

Phenotypic Responses

Abstract The water flea Daphnia magna is a keystone species in freshwater ecosystems and has been widely used as a model organism in environmental ecotoxicology. This aquatic crustacean is sensitive to environmental stressors and displays considerable plasticity in adapting to changing environmental conditions. Part of this plasticity may be due to epigenetic regulation of gene expression, including changes to DNA methylation and histone modifications. Because of the generally hypomethylated genome of this species, we hypothesized that the histone code may have an essential role in the epigenetic control and that histone modifications might be an early marker for stress. This study aims to characterize the epigenetic, transcriptional and phenotypic responses and their causal linkages in directly exposed adult (F0) Daphnia and peritoneal exposed neonates (F1) after a chronic (7-day) exposure to a sublethal concentration (10 mg/l) of 5-azacytidine, a well-studied vertebrate DNA methylation inhibitor. Exposure of the F0 generation significantly reduced the cumulative fecundity, accompanied with differential expression of genes in the one-carbon-cycle metabolic pathway. In the epigenome of the F0 generation, a decrease in global DNA methylation, but no significant changes on H3K4me3 or H3K27me3, were observed. In the F1 offspring generation, changes in gene expression, a significant reduction in global DNA methylation and changes in histone modifications were identified. The results indicate that exposure during adulthood may result in more pronounced effects on early development in the offspring generation, though interpretation of the data should be carefully done since both the exposure regime and developmental period is different in the two generations examined. The obtained results improve our understanding of crustacean epigenetics and the tools developed may promote use of epigenetic markers in hazard assessment of environmental stressors.

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Prioritizing putative influential genes in early life cardiovascular disease susceptibility by applying tissue-specific Mendelian randomization

10.1101/298687 ◽

2018 ◽

Author(s):

Kurt Taylor ◽

George Davey Smith ◽

Caroline L Relton ◽

Tom R Gaunt ◽

Tom G Richardson

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Disease Susceptibility ◽

Mendelian Randomization ◽

Analytical Framework ◽

Specific Gene ◽

Multiple Trait ◽

Trait Variation ◽

Tissue Specific ◽

Insight Into

AbstractBackgroundThe extent to which changes in gene expression can influence cardiovascular disease risk across different tissue types has not yet been systematically explored. We have developed an analytical framework that integrates tissue-specific gene expression, Mendelian randomization and multiple-trait colocalization to develop functional mechanistic insight into the causal pathway from genetic variant to complex trait.MethodsWe undertook a transcriptome-wide association study in a population of young individuals to uncover genetic variants associated with both nearby gene expression and cardiovascular traits. Two-sample Mendelian randomization was then applied using large-scale datasets to investigate whether changes in gene expression within certain tissue types may influence cardiovascular trait variation. We subsequently performed Bayesian multiple-trait colocalization to further interrogate findings and also gain insight into whether DNA methylation, as well as gene expression, may play a role in disease susceptibility.ResultsEight genetic loci were associated with changes in gene expression and early life measures of cardiovascular function. Our Mendelian randomization analysis provided evidence of tissue-specific effects at multiple loci, of which the effects at theADCY3andFADS1loci for body mass index and cholesterol respectively were particularly insightful. Multiple trait colocalization uncovered evidence which suggested that changes in DNA methylation at the promoter region upstream ofFADS1/TMEM258may also play a role in cardiovascular trait variation along with gene expression. Furthermore, colocalization analyses were able to uncover evidence of tissue-specificity, most prominantly betweenSORT1expression in liver tissue and cholesterol levels.ConclusionsDisease susceptibility can be influenced by differential changes in tissue-specific gene expression and DNA methylation. Our analytical framework should prove valuable in elucidating mechanisms in disease, as well as helping prioritize putative causal genes at associated loci where multiple nearby genes may be co-regulated. Future studies which continue to uncover quantitative trait loci for molecular traits across various tissue and cell typse will further improve our capability to understand and prevent disease.

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