A varying T cell subtype explains apparent tobacco smoking induced single CpG hypomethylation in whole blood

Bauer, Mario; Linsel, G.; Fink, Beate; Offenberg, Kirsten; Hahn, Anne M.; Sack, Ulrich; Knaack, Heike; Eszlinger, Markus; Herberth, Gunda

doi:10.1186/s13148-015-0113-1

Cited by 73 publications

(76 citation statements)

References 29 publications

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“…15 It is worth to note that the significant difference in methylation status of genes found in the peripheral blood of breast cancer patients may be affected by the change in population of different types of WBCs as previously described by the effects of tobacco on peripheral blood hypomethylation. 72 Nonetheless, we found some hypermethylated genes in WBCs of breast cancer patients including APC, HDAC1, BRCA1, and GSK1 whose hypermethylation pattern has been previously reported in more than one studies of breast cancer tissues. Replication of the same gene methylation pattern in different sample types and patients' race may highlight the critical epigenetic changes of those genes toward their under-expression leading to cancer progression.…”

Section: Discussionmentioning

confidence: 89%

Methylomics of breast cancer: Seeking epimarkers in peripheral blood of young subjects

et al. 2017

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Critical roles of epigenomic alterations in the pathogenesis of breast cancer have recently seized great attentions toward finding epimarkers in either non-invasive or semi-non-invasive samples as well as peripheral blood. In this way, methylated DNA immunoprecipitation microarray (MeDIP-chip) was performed on DNA samples isolated from white blood cells of 30 breast cancer patients compared to 30 healthy controls. A total of 1799 differentially methylated regions were identified including SLC6A3, Rab40C, ZNF584, and FOXD3 whose significant methylation differences were confirmed in breast cancer patients through quantitative real-time polymerase chain reaction. Hypermethylation of APC, HDAC1, and GSK1 genes has been previously reported in more than one study on tissue samples of breast cancer. Methylation of those aforementioned genes in white blood cells of our young patients not only relies on their importance in breast cancer pathogenesis but also may highlight their potential as early epimarkers that makes further assessments necessary in large cohort studies.

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Section: Discussionmentioning

confidence: 89%

Methylomics of breast cancer: Seeking epimarkers in peripheral blood of young subjects

et al. 2017

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“…However, we cannot exclude the possibility that the overlap of gene expression and DNA methylation change in relation to smoking may be due to changes in white blood cell types. A recent study by Bauer et al suggested that smokingrelated differential methylation and expression of GPR15 results from the enrichment of a smoking-induced lymphocyte population (42).…”

Section: Discussionmentioning

confidence: 99%

A Whole-Blood Transcriptome Meta-Analysis Identifies Gene Expression Signatures of Cigarette Smoking

et al. 2016

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Cigarette smoking is a leading modifiable cause of death worldwide. We hypothesized that cigarette smoking induces extensive transcriptomic changes that lead to target-organ damage and smoking-related diseases. We performed a metaanalysis of transcriptome-wide gene expression using whole blood-derived RNA from 10,233 participants of European ancestry in six cohorts (including 1421 current and 3955 former smokers) to identify associations between smoking and altered gene expression levels. At a false discovery rate (FDR) <0.1, we identified 1270 differentially expressed genes in current vs. never smokers, and 39 genes in former vs. never smokers. Expression levels of 12 genes remained elevated up to 30 years after smoking cessation, suggesting that the molecular consequence of smoking may persist for decades. Gene ontology analysis revealed enrichment of smoking-related genes for activation of platelets and lymphocytes, immune response, and apoptosis. Many of the top smoking-related differentially expressed genes, including LRRN3 and GPR15, have DNA methylation loci in promoter regions that were recently reported to be hypomethylated among smokers. By linking differential gene expression with smoking-related disease phenotypes, we demonstrated that stroke and pulmonary function show enrichment for smoking-related gene expression signatures. Mediation analysis revealed the expression of several genes (e.g. ALAS2) to be putative mediators of the associations between smoking and inflammatory biomarkers (IL6 and C-reactive protein levels). Our transcriptomic study provides potential insights into the effects of cigarette smoking on gene expression in whole blood and their relations to smoking-related diseases. The results of such analyses may highlight attractive targets for treating or preventing smoking-related health effects.

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“…As demonstrated convincingly by Bauer et al (2015), 76 associations of small changes in DNA methylation of specific loci associated with environmental exposures can be explained by exposure-associated changes in the leukocyte composition. The authors show that smoking-associated alterations of a CD3 lymphocyte subtype explain the reports by multiple authors of tobacco-associated DNA methylation alterations at the GPR15 locus.…”

Section: Implications For Population-based Research and Therapeuticsmentioning

confidence: 97%

The DNA methylation profile of activated human natural killer cells

et al. 2016

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Natural killer (NK) cells are now recognized to exhibit characteristics akin to cells of the adaptive immune system. The generation of adaptive memory is linked to epigenetic reprogramming including alterations in DNA methylation. The study herein found reproducible genome wide DNA methylation changes associated with human NK cell activation. Activation led predominately to CpG hypomethylation (81% of significant loci). Bioinformatics analysis confirmed that non-coding and gene-associated differentially methylated sites (DMS) are enriched for immune related functions (i.e., immune cell activation). Known DNA methylation-regulated immune loci were also identified in activated NK cells (e.g., TNFA, LTA, IL13, CSF2). Twenty-one loci were designated high priority and further investigated as potential markers of NK activation. BHLHE40 was identified as a viable candidate for which a droplet digital PCR assay for demethylation was developed. The assay revealed high demethylation in activated NK cells and low demethylation in na€ ıve NK, T-and B-cells. We conclude the NK cell methylome is plastic with potential for remodeling. The differentially methylated region signature of activated NKs revealed similarities with T cell activation, but also provided unique biomarker candidates of NK activation, which could be useful in epigenome-wide association studies to interrogate the role of NK subtypes in global methylation changes associated with exposures and/or disease states.

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A varying T cell subtype explains apparent tobacco smoking induced single CpG hypomethylation in whole blood

Cited by 73 publications

References 29 publications

Methylomics of breast cancer: Seeking epimarkers in peripheral blood of young subjects

Methylomics of breast cancer: Seeking epimarkers in peripheral blood of young subjects

A Whole-Blood Transcriptome Meta-Analysis Identifies Gene Expression Signatures of Cigarette Smoking

The DNA methylation profile of activated human natural killer cells

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