Download LONG-TERM EPIGENETIC EFFECTS AFTER PRENATAL

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, SCK•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).