Epigenetics Insights最新文献

{"title":"Maternal Microdeletion at the <i>H19/Igf2</i> ICR in Mice Increases Offspring Susceptibility to <i>In Utero</i> Environmental Perturbation.","authors":"Anandita Pal, Judy Oakes, Marwa Elnagheeb, Folami Y Ideraabdullah","doi":"10.1177/2516865720970575","DOIUrl":"10.1177/2516865720970575","url":null,"abstract":"<p><p>Deficiency of methyl donor nutrients folate, choline, and methionine (methyl deficiency) during gestation can impair fetal development and perturb DNA methylation. Here, we assessed genetic susceptibility to methyl deficiency by comparing effects in wildtype C57BL/6J (B6) mice to mutant mice carrying a 1.3 kb deletion at the <i>H19/Igf2</i> Imprinting Control Region (ICR) (<i>H19</i> ^ICRΔ2,3). The <i>H19</i> ^ICRΔ2,3 mutation mimics microdeletions observed in Beckwith-Wiedemann syndrome (BWS) patients, who exhibit epimutations in <i>cis</i> that cause loss of imprinting and fetal overgrowth. Dams were treated during pregnancy with 1 of 4 methyl sufficient (MS) or methyl deficient (MD) diets, with or without the antibiotic commonly used to deplete folate producing gut microbes. As expected, after ~9 weeks of treatment, dams in MD and MD + antibiotic groups exhibited substantially reduced plasma folate concentrations. <i>H19</i> ^ICRΔ2,3 mutant lines were more susceptible to adverse pregnancy outcomes caused by methyl deficiency (reduced birth rate and increased pup lethality) and antibiotic (decreased litter size and litter survival). Surprisingly, pup growth/development was only minimally affected by methyl deficiency, while antibiotic treatment caused inverse effects on B6 and <i>H19</i> ^ICRΔ2,3 lines. B6 pups treated with antibiotic exhibited increased neonatal and weanling bodyweight, while both wildtype and mutant pups of heterozygous <i>H19</i> ^ICRΔ2,3/+ dams exhibited decreased neonatal bodyweight that persisted into adulthood. Interestingly, only antibiotic-treated pups carrying the <i>H19</i> ^ICRΔ2,3 mutation exhibited altered DNA methylation at the <i>H19/Igf2</i> ICR, suggesting ICR epimutation was not sufficient to explain the altered phenotypes. These findings demonstrate that genetic mutation of the <i>H19/Igf2</i> ICR increases offspring susceptibility to developmental perturbation in the methyl deficiency model, maternal and pup genotype play an essential role, and antibiotic treatment in the model also plays a key independent role.</p>","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2020-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/df/25/10.1177_2516865720970575.PMC7716063.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38705843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Site-Specific DNA Demethylation as a Potential Target for Cancer Epigenetic Therapy.","authors":"Sultan Abda Neja","doi":"10.1177/2516865720964808","DOIUrl":"https://doi.org/10.1177/2516865720964808","url":null,"abstract":"<p><p>Aberrant promoter DNA hypermethylation is a typical characteristic of cancer and it is often seen in malignancies. Recent studies showed that regulatory cis-elements found up-stream of many tumor suppressor gene promoter CpG island (CGI) attract DNA methyltransferases (DNMT) that hypermethylates and silence the genes. As epigenetic alterations are potentially reversible, they make attractive targets for therapeutic intervention. The currently used decitabine (DAC) and azacitidine (AZA) are DNMT inhibitors that follow the passive demethylation pathway. However, they lead to genome-wide demethylation of CpGs in cells, which makes difficult to use it for causal effect analysis and treatment of specific epimutations. Demethylation through specific demethylase enzymes is thus critical for epigenetic resetting of silenced genes and modified chromatins. Yet DNA-binding factors likely play a major role to guide the candidate demethylase enzymes upon its fusion. Before the advent of clustered regulatory interspaced short palindromic repeats (CRISPR), both zinc finger proteins (ZNFs) and transcription activator-like effector protein (TALEs) were used as binding platforms for ten-eleven translocation (TET) enzymes and both systems were able to induce transcription at targeted loci in an <i>in vitro</i> as well as <i>in vivo</i> model. Consequently, the development of site-specific and active demethylation molecular trackers becomes more than hypothetical to makes a big difference in the treatment of cancer in the future. This review is thus to recap the novel albeit distinct studies on the potential use of site-specific demethylation for the development of epigenetic based cancer therapy.</p>","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2020-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2516865720964808","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39827856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>E-Cadherin, NFATC3</i>, and <i>PLP2</i> Are Differentially Methylated in Multiple Cancers.","authors":"Mary J Lotesto,&nbsp;Christopher J Wallace,&nbsp;Stacey L Raimondi","doi":"10.1177/2516865720964802","DOIUrl":"https://doi.org/10.1177/2516865720964802","url":null,"abstract":"<p><p>It is well documented that cancer cells have abnormal methylation patterns often caused by faulty methylating machinery. Specifically, <i>E-cadherin, NFATC3</i>, and <i>PLP2</i> are 3 genes known to be aberrantly methylated in cancer cells. These genes are well documented for their role in signaling pathways involved with cell proliferation, adhesion, migration, and other signs of tumor progression. Therefore, changes in gene expression of <i>CDH1, NFATC3</i>, and <i>PLP2</i> due to aberrant methylation can lead to profound changes in cellular function and tumor formation. In order to ensure that previous <i>in vitro</i> and <i>in vivo</i> methylation studies match what is observed in the clinic, we utilized a bioinformatics approach to complete an extensive analysis of methylation patterns of these 3 genes, analyzing over 5000 patient samples, across all cancers for which both normal and tumor tissues were available. Specifically, we analyzed overall and site-specific methylation patterns, at CpG islands and shores, of all 3 genes across 14 cancer types. Furthermore, we compared these methylation levels in normal and tumor samples of both matched and unmatched patient samples in order to determine any differences between groups. Finally, we examined whether an aberrant DNA methyltransferase, <i>DNMT3B7</i>, known to be expressed in cancer cells and to alter methylation patterns <i>in vitro</i> correlated with altered overall and site-specific methylation of <i>CDH1, NFATC3</i>, and <i>PLP2</i> in these patient samples. Our results indicate that methylation patterns of <i>CDH1</i> and <i>NFATC3</i> were unexpectedly varied across tumors, contrary to previous studies performed <i>in vitro</i>, while <i>PLP2</i> showed the expected hypomethylation pattern in tumor tissues. We also observed some correlation between <i>DNMT3B7</i> expression and methylation patterns of these genes, but patterns were inconsistent. Taken together, these results emphasize the necessity for <i>in vivo</i> and patient studies rather than a complete reliance on <i>in vitro</i> data and provide multiple areas of future research.</p>","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2020-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2516865720964802","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38593823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA Methylation of Endoglin Pathway Genes in Pregnant Women With and Without Preeclampsia.","authors":"Allison H Rietze,&nbsp;Yvette P Conley,&nbsp;Dianxu Ren,&nbsp;Cindy M Anderson,&nbsp;James M Roberts,&nbsp;Arun Jeyabalan,&nbsp;Carl A Hubel,&nbsp;Mandy J Schmella","doi":"10.1177/2516865720959682","DOIUrl":"https://doi.org/10.1177/2516865720959682","url":null,"abstract":"<p><strong>Objective: </strong>We compared blood-based DNA methylation levels of endoglin (<i>ENG</i>) and transforming growth factor beta receptor 2 (<i>TGFβR2</i>) gene promoter regions between women with clinically-overt preeclampsia and women with uncomplicated, normotensive pregnancies.</p><p><strong>Methods: </strong>We used EpiTect Methyl II PCR Assays to evaluate DNA methylation of CpG islands located in promoter regions of <i>ENG</i> (CpG Island 114642) and <i>TGFβR2</i> (CpG Island 110111). Preeclampsia was diagnosed based on blood pressure, protein, and uric acid criteria. N = 21 nulliparous preeclampsia case participants were 1:1 frequency matched to N = 21 nulliparous normotensive control participants on gestational age at sample collection (±2 weeks), smoking status, and labor status at sample collection. Methylation values were compared between case and control participant groups [(<i>ENG</i> subset: n = 20 (9 cases, 11 controls); <i>TGFβR2</i> subset: n = 28 (15 cases, 13 controls)].</p><p><strong>Results: </strong>The majority of the preeclampsia cases delivered at ⩾34 weeks' gestation (83%). Average methylation levels for <i>ENG</i> ([M ± (SD)]; Case Participant Group = 6.54% ± 4.57 versus Control Participant group = 4.81% ± 5.08; <i>P</i> = .102) and <i>TGFβR2</i> (Case Participant Group = 1.50% ± 1.37 vs Control Participant Group = 1.70% ± 1.40; <i>P</i> = .695) promoter CpG islands did not differ significantly between the participant groups. Removal of 2 extreme outliers in the <i>ENG</i> analytic subset revealed a trend between levels of <i>ENG</i> methylation and pregnancy outcome (Case Participant Group = 5.17% ± 2.16 vs Control Participant Group = 3.36% ± 1.73; <i>P</i> = .062).</p><p><strong>Conclusion: </strong>Additional epigenetic studies that include larger sample sizes, investigate preeclampsia subtypes, and capture methylation status of CpG island shores and shelves are needed to further inform us of the potential role that <i>ENG</i> and <i>TGFβR2</i> DNA methylation plays in preeclampsia pathophysiology.</p>","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2020-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2516865720959682","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38527886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Influence of Woodsmoke Exposure on Molecular Mechanisms Underlying Alzheimer's Disease: Existing Literature and Gaps in Our Understanding.","authors":"Adam Schuller,&nbsp;Luke Montrose","doi":"10.1177/2516865720954873","DOIUrl":"https://doi.org/10.1177/2516865720954873","url":null,"abstract":"<p><p>Woodsmoke poses a significant health risk as a growing component of ambient air pollution in the United States. While there is a long history of association between woodsmoke exposure and diseases of the respiratory, circulatory, and cardiovascular systems, recent evidence has linked woodsmoke exposure to cognitive dysfunction, including Alzheimer's disease dementia. Alzheimer's disease is a progressive neurodegenerative disorder with largely idiopathic origins and no known cure. Here, we explore the growing body of literature which relates woodsmoke-generated and ambient air pollution particulate matter exposure to Alzheimer's disease (AD) onset or exacerbation, in the context of an inflammation-centric view of AD. Epigenetic modifications, specifically changes in DNA methylation patterns, are well documented following woodsmoke exposure and have been shown to influence disease-favoring inflammatory cascades, induce oxidative stress, and modulate the immune response in vitro, in vivo, and in humans following exposure to air pollution. Though the current status of the literature does not allow us to draw definitive conclusions linking these events, this review highlights the need for additional work to fill gaps in our understanding of the directionality, causality, and susceptibility throughout the life course.</p>","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2020-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2516865720954873","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38418597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of DNA Methylation in Transcriptional Regulation of Pro-Nociceptive Genes in Rat Trigeminal Ganglia.","authors":"Guang Bai,&nbsp;Holly Ross,&nbsp;Youping Zhang,&nbsp;KiSeok Lee,&nbsp;Jin Y Ro","doi":"10.1177/2516865720938677","DOIUrl":"https://doi.org/10.1177/2516865720938677","url":null,"abstract":"<p><p>Epigenetic modulation by DNA methylation is associated with aberrant gene expression in sensory neurons, which consequently leads to pathological pain responses. In this study, we sought to investigate whether peripheral inflammation alters global DNA methylation in trigeminal ganglia (TG) and results in abnormal expression of pro-nociceptive genes. Our results show that peripheral inflammation remotely reduced the level of global DNA methylation in rat TG with a concurrent reduction in <i>DNMT1</i> and <i>DNMT3a</i> expression. Using unbiased steps, we selected the following pro-nociceptive candidate genes that are potentially regulated by DNA methylation: <i>TRPV1, TRPA1, P2X3</i>, and <i>PIEZO2</i>. Inhibition of DNMT with 5-Aza-dC in dissociated TG cells produced dose-dependent upregulation of <i>TRPV1, TRPA1</i>, and <i>P2X3</i>. Systemic treatment of animals with 5-Aza-dC significantly increased the expression of <i>TRPV1, TRPA1</i>, and <i>PIEZO2</i> in TG. Furthermore, the overexpression of DNMT3a, as delivered by a lentiviral vector, significantly downregulated <i>TRPV1</i> and <i>PIEZO2</i> expression and also reliably decreased <i>TRPA1</i> and <i>P2X3</i> transcripts. MeDIP revealed that this overexpression also significantly enhanced methylation of CGIs associated with <i>TRPV1</i> and <i>TRPA1</i>. In addition, bisulfite sequencing data indicated that the CGI associated with <i>TRPA1</i> was methylated in a pattern catalyzed by DNMT3a. Taken together, our results show that all 4 pro-nociceptive genes are subject to epigenetic modulation via DNA methylation, likely via DNMT3a under inflammatory conditions. These findings provide the first evidence for the functional importance of DNA methylation as an epigenetic factor in the transcription of pro-nociceptive genes in TG that are implicated in pathological orofacial pain responses.</p>","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2020-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2516865720938677","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38418158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paternal DNA Methylation May Be Associated With Gestational Age at Birth.","authors":"Rui Luo,&nbsp;Nandini Mukherjee,&nbsp;Su Chen,&nbsp;Yu Jiang,&nbsp;S Hasan Arshad,&nbsp;John W Holloway,&nbsp;Anna Hedman,&nbsp;Olena Gruzieva,&nbsp;Ellika Andolf,&nbsp;Goran Pershagen,&nbsp;Catarina Almqvist,&nbsp;Wilfried Jj Karmaus","doi":"10.1177/2516865720930701","DOIUrl":"https://doi.org/10.1177/2516865720930701","url":null,"abstract":"<p><strong>Background: </strong>How epigenetic modifications of DNA are associated with gestational age at birth is not fully understood. We investigated potential effects of differential paternal DNA methylation (DNAm) on offspring gestational age at birth by conducting an epigenome-wide search for cytosine-phosphate-guanine (CpG) sites.</p><p><strong>Methods: </strong>Study participants in this study consist of male cohort members or partners of the F1-generation of the Isle of Wight Birth Cohort (IoWBC). DNAm levels in peripheral blood from F1-fathers (n = 92) collected around pregnancy of their spouses were analyzed using the Illumina 450K array. A 5-step statistical analysis was performed. First, a training-testing screening approach was applied to select CpG sites that are potentially associated with gestational age at birth. Second, functional enrichment analysis was employed to identify biological processes. Third, by centralizing on biologically informative genes, Cox proportional hazards models were used to assess the hazard ratios of individual paternal CpGs on gestational age adjusting for confounders. Fourth, to assess the validity of our results, we compared our CpG-gestational age correlations within a Born into Life Study in Sweden (n = 15). Finally, we investigated the correlation between the detected CpGs and differential gene expression in F2 cord blood in the IoWBC.</p><p><strong>Results: </strong>Analysis of DNAm of fathers collected around their partner's pregnancy identified 216 CpG sites significantly associated with gestational age at birth. Functional enrichment pathways analyses of the annotated genes revealed 2 biological pathways significantly related to cell-cell membrane adhesion molecules. Differential methylation of 9 cell membrane adhesion pathway-related CpGs were significantly associated with gestational age at birth after adjustment for confounders. The replication sample showed correlation coefficients of 2 pathway-related CpGs with gestational age at birth within 95% confidence intervals of correlation coefficients in IoWBC. Finally, CpG sites of protocadherin (<i>PCDH</i>) gene clusters were associated with gene expression of <i>PCDH</i> in F2 cord blood.</p><p><strong>Conclusions: </strong>Our findings suggest that differential paternal DNAm may affect gestational age at birth through cell-cell membrane adhesion molecules. The results are novel but require future replication in a larger cohort.</p>","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2020-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2516865720930701","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38411572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Understudied Dimension: Why Age Needs to Be Considered When Studying Epigenetic-Environment Interactions.","authors":"Rio Barrere-Cain,&nbsp;Patrick Allard","doi":"10.1177/2516865720947014","DOIUrl":"https://doi.org/10.1177/2516865720947014","url":null,"abstract":"<p><p>We live in a complex chemical environment where there are an estimated 350 000 chemical compounds or mixtures commercially produced. A strong body of literature shows that there are time points during early development when an organism's epigenome is particularly sensitive to chemicals in its environment. What is less understood is how gene-environment and epigenetic-environment interactions change with age. This question is bidirectional: (1) how do chemicals in the environment affect the aging process and (2) how does aging affect an organism's response to its chemical environment? The study of gene-environment interactions with age is especially important because, in many parts of the world, older individuals are a large and rapidly growing proportion of the population and because aging is a process universal to most of the animal kingdom. Epigenetics has emerged as a crucial framework for studying aging as epigenetic pathways, often triggered by environmental stimuli, have been shown to be essential regulators of the aging process. In this perspective article, we delineate the connection between aging, epigenetics, and environmental exposures. We discuss why it is essential to consider age when researching how an organism interacts with its environment. We describe recent advances in understanding how the chemical environment affects aging and the gap in research on how age affects an organism's response to the environment. Finally, we highlight how model organisms and network approaches can help fill this crucial gap. Taken together, systemic changes that occur in the epigenome with age indicate that adult organisms cannot be treated as a homogeneous population and that there are discrete mechanisms modulating the aging epigenome that we do not yet understand.</p>","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2020-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2516865720947014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38421576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-Specific Programming of Cardiac DNA Methylation by Developmental Phthalate Exposure.","authors":"Laurie K Svoboda,&nbsp;Kai Wang,&nbsp;Raymond G Cavalcante,&nbsp;Kari Neier,&nbsp;Justin A Colacino,&nbsp;Maureen A Sartor,&nbsp;Dana C Dolinoy","doi":"10.1177/2516865720939971","DOIUrl":"https://doi.org/10.1177/2516865720939971","url":null,"abstract":"<p><p>Phthalate plasticizers are ubiquitous chemicals linked to several cardiovascular diseases in animal models and humans. Despite this, the mechanisms by which phthalate exposures cause adverse cardiac health outcomes are unclear. In particular, whether phthalate exposures during pregnancy interfere with normal developmental programming of the cardiovascular system, and the resulting implications this may have for long-term disease risk, are unknown. Recent studies suggest that the effects of phthalates on metabolic and neurobehavioral outcomes are sex-specific. However, the influence of sex on cardiac susceptibility to phthalate exposures has not been investigated. One mechanism by which developmental exposures may influence long-term health is through altered programming of DNA methylation. In this work, we utilized an established mouse model of human-relevant perinatal exposure and enhanced reduced representation bisulfite sequencing to investigate the long-term effects of diethylhexyl phthalate (DEHP) exposure on DNA methylation in the hearts of adult male and female offspring at 5 months of age (n = 5-7 mice per sex and exposure). Perinatal DEHP exposure led to hundreds of sex-specific, differentially methylated cytosines (DMCs) and differentially methylated regions (DMRs) in the heart. Pathway analysis of DMCs revealed enrichment for several pathways in females, including insulin signaling, regulation of histone methylation, and tyrosine phosphatase activity. In males, DMCs were enriched for glucose transport, energy generation, and developmental programs. Notably, many sex-specific genes differentially methylated with DEHP exposure in our mouse model were also differentially methylated in published data of heart tissues collected from human heart failure patients. Together, these data highlight the potential role for DNA methylation in DEHP-induced cardiac effects and emphasize the importance of sex as a biological variable in environmental health studies.</p>","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2020-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2516865720939971","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38421575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interweaving Between Genetic and Epigenetic Studies on Childhood Asthma.","authors":"Aniruddha Rathod,&nbsp;Jiasong Duan,&nbsp;Hongmei Zhang,&nbsp;John W Holloway,&nbsp;Susan Ewart,&nbsp;S Hasan Arshad,&nbsp;Wilfried Karmaus","doi":"10.1177/2516865720923395","DOIUrl":"https://doi.org/10.1177/2516865720923395","url":null,"abstract":"<p><p>The cause and underlying mechanisms that contribute to asthma pathogenesis are not well known. Both genome- and epigenome-wide association studies have identified genes associated with asthma risk. It is unknown to what extent genes identified in these two types of studies overlap. Based on existing literature and the DisGeNET database, we extracted overlapping genes identified in genetic and epigenetic studies of childhood asthma. Through analyses of variance, we assessed whether DNA methylation (DNAm) at 5'-C-phosphate-G-3' (CpGs) on the overlapping genes was associated with neighboring single-nucleotide polymorphisms (SNPs) within 1M base pairs (bps) and with low linkage disequilibrium (<i>r</i> ² <i><</i> 0.2) in the childhood asthma-related genes. In total, 285 genes from genetic studies and 226 genes from epigenetic studies were shown to be associated with asthma risk, of which six overlap. Of the six genes, 79 CpGs and 8229 unique neighboring SNPs (1M bps) were included in methylation quantitative loci (methQTL) assessment analyses. We tested the association of DNAm at each of the 79 CpG sites with its neighboring SNPs. After adjusting for multiple testing by controlling the false discovery rate to 0.05 when testing methQTL for each CpG site, we found statistically significant associations in three genes with their neighboring SNPs and identified 34 unique methQTLs. The rather limited overlap in genes between genetic and epigenetic studies on asthma and the absence of methQTL in some of the overlapping genes highlight a need to jointly, rather than independently, examine genetic and epigenetic effects on asthma risk to improve our understanding of the underlying mechanisms of asthma.</p>","PeriodicalId":41996,"journal":{"name":"Epigenetics Insights","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2020-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2516865720923395","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38228969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}