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LONG-TERM EPIGENETIC EFFECTS AFTER PRENATAL RADIATION EXPOSURE OF THE MOUSE BRAIN Roel Quintens1, Tine Verreet1,2, Mieke Verslegers1, Mieke Neefs1, Liselotte Leysen1, Ann Janssen1, Arlette Michaux1, Sarah Baatout1, M. Abderrafi Benotmane 1 Radiobiology Unit, Molecular and Cellular Biology, Belgian Nuclear Research Centre, SCKā¢CEN, Mol, Belgium 2 Laboratory of Neural Circuit Development and Regeneration, University of Leuven, KU Leuven, Leuven, Belgium [email protected] Epidemiological studies of Hiroshima/Nagazaki A-bomb survivors, as well as animal studies have shown that in utero radiation exposure can lead to mental retardation and cognitive defects, respectively. We observed that exposure of pregnant mice at E11 to low (20 and 100 mGy) and moderate (500 and 1000 mGy) doses of ionizing radiation leads to dose-dependent cognitive and behavioural deficits at adult age of in utero exposed mice. In this study, we analyzed genome-wide gene expression from different brain regions (cerebral cortex, cerebellum and hippocampus) of mice at the age of six months, in order to identify the molecular mechanisms of the long-term effects of prenatal radiation exposure. Our data indicate that after 6 months, epigenetic mechanisms have been initiated in the radiation-exposed brains. Especially in the cortex, we find a significant, dosedependent increase (about 2-fold in 1000 mGy-irradiated mice) in expression of a number of long non-coding RNAs and microRNAs belonging to an imprinted gene cluster which is normally transcribed from the maternal chromosome. The imprinted status of this cluster is regulated by several differentially methylated regions (DMRs) which are methylated in the paternal allele, resulting in maternal-specific expression. Our data therefore suggest that the methylation status of the DMR(s) on the paternal chromosome has changed after irradiation, leading to the loss of imprinting and therefore a doubling of the gene dosage of these genes. Interestingly, the non-coding RNAs of this region are especially highly expressed in the adult brain, whereas the induced microRNAs are predicted to preferentially target genes involved in brainspecific functions. Furthermore, several of these microRNAs have been shown to be dysregulated after fetal alcohol exposure, which is also known to result in behavioural defects at adult age. This, together, suggests that epigenetic changes in ncRNAs which are important for normal brain function are responsible for the long-term behavioural effects of prenatal radiation exposure. Acknowledgements: This work is supported by the EU-FP7 project CEREBRAD (n° 295552).