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Global delay in nascent strand DNA methylation.

ABSTRACT: Cytosine methylation is widespread among organisms and essential for mammalian development. In line with early postulations of an epigenetic role in gene regulation, symmetric CpG methylation can be mitotically propagated over many generations with extraordinarily high fidelity. Here, we combine BrdU labeling and immunoprecipitation with genome-wide bisulfite sequencing to explore the inheritance of cytosine methylation onto newly replicated DNA in human cells. Globally, we observe a pronounced lag between the copying of genetic and epigenetic information in embryonic stem cells that is reconsolidated within hours to accomplish faithful mitotic transmission. Populations of arrested cells show a global reduction of lag-induced intermediate CpG methylation when compared to proliferating cells, whereas sites of transcription factor engagement appear cell-cycle invariant. Alternatively, the cancer cell line HCT116 preserves global epigenetic heterogeneity independently of cell-cycle arrest. Taken together, our data suggest that heterogeneous methylation largely reflects asynchronous proliferation, but is intrinsic to actively engaged cis-regulatory elements and cancer.

SUBMITTER: Charlton J

PROVIDER: S-EPMC5889353 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Global delay in nascent strand DNA methylation.

Charlton Jocelyn J Downing Timothy L TL Smith Zachary D ZD Gu Hongcang H Clement Kendell K Pop Ramona R Akopian Veronika V Klages Sven S Santos David P DP Tsankov Alexander M AM Timmermann Bernd B Ziller Michael J MJ Kiskinis Evangelos E Gnirke Andreas A Meissner Alexander A

Nature structural & molecular biology 20180312 4

Cytosine methylation is widespread among organisms and essential for mammalian development. In line with early postulations of an epigenetic role in gene regulation, symmetric CpG methylation can be mitotically propagated over many generations with extraordinarily high fidelity. Here, we combine BrdU labeling and immunoprecipitation with genome-wide bisulfite sequencing to explore the inheritance of cytosine methylation onto newly replicated DNA in human cells. Globally, we observe a pronounced ...[more]

PMID: 29531288

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Project description:Objectives: Early identification of smoking, essential for the successful implementation of interventions, arrests the escalation of smoking and smoking-associated risk behaviors in adolescents. However, because nascent smoking is typically episodic and infrequent, enzyme-linked immunoassay reagent-based approaches that detect cotinine, a key nicotine metabolite, are not effective in identifying adolescents in the earliest stages of smoking. Epigenetic methods may offer an alternative approach for detecting early-stage smokers. In prior work, we and others have shown that the methylation status of cg05575921 of whole-blood DNA accurately predicts smoking status in regularly smoking adults and is sensitive to nascent smoking. Yet, the blood draws necessary to obtain DNA for this method may be poorly accepted by adolescents. Saliva could be an alternative source of DNA. However, the ability of saliva DNA methylation status to predict smoking status among adolescents is unknown. Methods: To explore the possibility of using salivary DNA for screening purposes, we examined the DNA methylation status at cg05575921 in saliva DNA samples from 162 high school aged subjects for whom we also had paired serum cotinine values. Results: Overall, the reliability of self-report of nicotine/tobacco use in these adolescents was poor with 67% of all subjects whose serum levels of cotinine was ?2?ng/mL (n?=?75) denying any use of nicotine-containing products in the past 6 months. However, the correspondence of the two biological measures of smoking was high, with serum cotinine positivity being strongly correlated with cg05575921 methylation (p?<?0.0001). Receiver operating characteristic (ROC) analyses showed that cg05575921 methylation status could be used to classify those with positive serum cotinine values (?2?ng/mL) from those denying smoking and have undetectable levels of cotinine. Conclusions: We conclude that saliva DNA methylation assessments hold promise as a means of detecting nascent smoking.

Dataset Information

Global delay in nascent strand DNA methylation.

Publications

Global delay in nascent strand DNA methylation.

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