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Single-promoter analysis of CpG and non-CpG methylation patterns in spleen of mice exposed to extremely low frequency magnetic field (ELF-MF)

: Reamon-Buettner, Stella Marie; Hiemisch, Andreas; Lewin, Geertje; Dasenbrock, Clemens; Halter, Roman

Naunyn-Schmiedebergs archives of pharmacology 388 (2015), Supplement 1, S.S56
ISSN: 0028-1298
ISSN: 1432-1912
Deutsche Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikologie (Annual Meeting) <81, 2015, Kiel>
Konferenzbeitrag, Zeitschriftenaufsatz
Fraunhofer ITEM ()

Exposures to extremely low frequency magnetic field (ELF-MF) may lead to disruptions of the genome and epigenome leading to childhood leukemia. Thus, in the EU-funded project ARIMMORA, we analyzed genes implicated in leukemia for aberrant transcriptomic, genetic, and epigenetic changes. These genes include cell adhesion molecule 1 (Cadm1), a tumor suppressor gene frequently inactivated in human cancer by promoter hypermethylation. We investigated by bisulfite sequencing and cloning, a 349-bp fragment encompassing 37 CpGs along the promoter and 5'-UTR regions of Cadm1 in spleen tissues of n = 10 female Crl:CD1 mice exposed for 90-days (20 h/d, 7 d/wk) starting on day 10 p.c. to 50Hz 10mT ELF-MF, and n = 10 respective shamexposed controls. CpG methylation pattern was heterogeneous within a spleen tissue, and among individual mice in both exposed and sham. Nevertheless, overall % methylation tended to be higher in 90-day exposed mice than in respective controls. Notably, we found clones exhibiting not only highly methylated CpGs but also non-CpGs, a finding reminiscent of stem cell nature or intriguing observation in the light of a recent report iPS reprogramming, and an (Baek et al. 2014)* that electromagnetic field can mediate efficient cell reprogramming into a pluripotent state. We found clones with this 'stem-cell pattern' in exposed 20/107 (19 %), and 7/94 (7 %) in sham-control mice. The non-CpG methylation was not random, but associated with highly methylated neighboring CpGs. Indeed, cytosines within two neighboring Sp1 binding sites and those cytosines within a nucleosome near the transcription start site (TSS) exhibited non-CpG methylation, consistent with the notion that the presence of non-CpG methylation ensure the stem-cell character by preventing the binding of proteins necessary for differentiation. We also detected n = 63 different sequence variations, of which 31 (49 %) in exposed mice, 19 (30 %) in control, and 13 (20 %) in both. Exposures to ELF-MF leading to reprogramming require further studies, and a single-cell or single-molecule approach would surely allow dissection of genetic and epigenetic changes resulting from ELF-MF exposures in intact tissues composed of a mixure of differentiated and stem cells, such as spleen. Determining sequence variations in clones with 'stem cell pattern' might provide additional insights into the potential risk of high-dose ELF-MF in leukemia development.