Differential DNA methylation and PM2.5 species in a 450K epigenome-wide association study
Lingzhen DaiAmar MehtaIrina MordukhovichAllan C. JustJincheng ShenLifang HouPetros KoutrakisDavid SparrowPantel VokonasAndrea BaccarelliJoel Schwartz
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Although there is growing evidence that exposure to ambient particulate matter is associated with global DNA methylation and gene-specific methylation, little is known regarding epigenome-wide changes in DNA methylation in relation to particles and, especially, particle components. Using the Illumina Infinium HumanMethylation450 BeadChip, we examined the relationship between one-year moving averages of PM2.5 species (Al, Ca, Cu, Fe, K, Na, Ni, S, Si, V, and Zn) and DNA methylation at 484,613 CpG probes in a longitudinal cohort that included 646 subjects. Bonferroni correction was applied to adjust for multiple comparisons. Bioinformatics analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment was also performed. We observed 20 Bonferroni significant (P-value < 9.4× 10−9) CpGs for Fe, 8 for Ni, and 1 for V. Particularly, methylation at Schlafen Family Member 11 (SLFN11) cg10911913 was positively associated with measured levels of all 3 species. The SLFN11 gene codes for an interferon-induced protein that inhibits retroviruses and sensitizes cancer cells to DNA-damaging agents. Bioinformatics analysis suggests that gene targets may be relevant to pathways including cancers, signal transduction, and cell growth and death. Ours is the first study to examine the epigenome-wide association between ambient particles species and DNA methylation. We found that long-term exposures to specific components of ambient particle pollution, especially particles emitted during oil combustion, were associated with methylation changes in genes relevant to immune responses. Our findings provide insight into potential biologic mechanisms on an epigenetic level.Keywords:
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Abstract: Epigenomes are comprised, in part, of all genome-wide chromatin modifications, including DNA methylation and histone modifications. Unlike the genome, epigenomes are dynamic during development and differentiation to establish and maintain cell type–specific gene expression states that underlie cellular identity and function. Chromatin modifications are particularly labile, providing a mechanism for organisms to respond and adapt to environmental cues. Results from studies in animal models clearly demonstrate that epigenomic variability leads to phenotypic variability, including susceptibility to disease that is not recognized at the DNA sequence level. Thus, capturing epigenomic information is invaluable for comprehensively understanding development, differentiation, and disease. Herein, we provide a brief overview of epigenetic processes, how they are relevant to human health, and review studies using technologies that enable epigenome mapping. We conclude by describing feasible applications of epigenome mapping, focusing on epigenome-wide association studies (eGWAS), which have the potential to revolutionize current studies of human diseases and will likely promote the discovery of novel diagnostic, preventative, and treatment strategies.
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Epigenetics is a gene regulation mechanism that does not depend on genomic DNA sequences but depends on chemical modification of genomic DNA and histone proteins around which DNA is wrapped. The failure of epigenetic mechanisms is known to cause various congenital disorders. It is also known that the failures of epigenetic mechanisms causes various acquired disorders since epigenetic modifications of the genome (i.e., "epigenome") are more vulnerable to environmental stress, such as malnutrition, environmental chemicals, and mental stress, than the "genome," especially during the early period of life. However, the epigenome has a reversible property since it is based on removable residues on genomic DNA. Thus, environmentally induced epigenomic alterations can be potentially restored. In fact, some medicines, especially for psychiatric diseases, are known to restore an altered epigenome, resulting in the correction of gene expression. Several lines of evidence suggest that environmentally induced epigenomic alterations are not erased completely during gametogenesis, but are transmitted to subsequent generations with disease phenotypes. In accordance with these understandings, I would like to propose the development of epigenomic-based preemptive medicine that consists of the early detection of the developmental origins of diseases using epigenomic signatures and the early intervention that take advantages of the use of epigenomic reversibility.
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Epigenomic modifications are unique in the type and amount of chemical modification at each chromosomal location, can vary from cell to cell, and can be externally modulated by small molecules. In recent years, genome-wide epigenomic modifications have been revealed, and rapid progress has been made in the identification of proteins responsible for epigenomic modifications and in the development of compounds that regulate them. This Special Issue on "Epidrugs: Toward Understanding and Treating Diverse Diseases" aims to provide insights into various aspects of the biology and development of epigenome-regulating compounds.
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It is tempting to assume that a gradual accumulation of damage 'causes' an organism to age, but other biological processes present during the lifespan, whether 'programmed' or 'hijacked', could control the type and speed of aging. Theories of aging have classically focused on changes at the genomic level; however, individuals with similar genetic backgrounds can age very differently. Epigenetic modifications include DNA methylation, histone modifications and ncRNA. Environmental cues may be 'remembered' during lifespan through changes to the epigenome that affect the rate of aging. Changes to the epigenomic landscape are now known to associate with aging, but so far causal links to longevity are only beginning to be revealed. Nevertheless, it is becoming apparent that there is significant reciprocal regulation occurring between the epigenomic levels. Future work utilizing new technologies and techniques should build a clearer picture of the link between epigenomic changes and aging.
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Abstract The role of the epigenome in phenotypic plasticity is unclear presently. Here we used a multiomics approach (RNA-seq, ChIP-seq, ATAC-seq and Hi-C) to explore the nature of the epigenome in developing honeybee (Apis mellifera) workers and queens. Our data showed that the distinct queen and worker epigenomic landscapes form during the developmental process. Differences in gene expression between workers and queens precede other epigenomic modifications, but the epigenomic differences between workers and queens become more extensive and more layered during development. Genes known to be important for caste differentiation were more likely to be multiply differentially regulated by more than one epigenomic system than other differentially expressed genes. This indicates a multidimensional regulation of expression of key genes, presumably to canalise differences in gene expression. Our data indicate that the epigenome interacts with diverging developmental trajectories rather than controlling them since different epigenomic landscapes form in concert with different developmental outcomes.
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Epigenetic modifications, DNA methylation and histone modifications, mark genes to be used and not to be used, and are stably inherited in somatic cells. Epigenome is their genome-wide compilation, and undergoes dynamic changes in development, differentiation, and reprogramming. Epigenomic changes are causally involved in cancer development and progression by inducing silencing of tumor-suppressor genes and genomic instability. Aberrant DNA methylation can accumulate in a large fraction of cells even in tissues without clonal lesions, which indicates that epigenomic changes can potentially affect functions of a tissue. Multiple reports show that epigenomic changes are present in acquired neurological, metabolic, and immunological disorders, and more research in the field is urgently necessary.
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An epigenome is a chemical modification pattern of genomic DNA that determines the on/off status of genes, and its abnormalities are known to cause congenital diseases. Recent studies have shown that epigenomic patterns are altered by various environmental factors, indicating that epigenomic abnormalities also cause acquired mental and neurological diseases. An epigenomic pattern that reflects past environmental insults is an epigenomic signature. Therefore, it will be used as a marker for preemptive medicine in that it is not based on the population but is instead based on individuals.
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It is undeniably one of the greatest findings in biology that (with some very minor exceptions) every cell in the body possesses the whole genetic information needed to generate a complete individual. Today, this concept has been so thoroughly assimilated that we struggle to still see how surprising this finding actually was: all cellular phenotypes naturally occurring in one person are generated from genetic uniformity, and thus are per definition epigenetic. Transcriptional mechanisms are clearly critical for developing and protecting cell identities, because a mis-expression of few or even single genes can efficiently induce inappropriate cellular programmes. However, how transcriptional activities are molecularly controlled and which of the many known epigenomic features have causal roles remains unclear. Today, clarification of this issue is more pressing than ever because profiling efforts and epigenome-wide association studies (EWAS) continuously provide comprehensive datasets depicting epigenomic differences between tissues and disease states. In this commentary, we propagate the idea of a widespread follow-up use of epigenome editing technology in EWAS studies. This would enable them to address the questions of which features, where in the genome, and which circumstances are essential to shape development and trigger disease states.
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