Alterations in genomically imprinted miRNA and snoRNA clusters in a mouse model of fetal alcohol spectrum disorders. B. I. Laufer, K. Mantha, M. L. Kleiber, E. J. Diehl, S. M. F. Addison, S. M. Singh Molecular Genetics Unit, University of Western Ontario, London, Ontario, Canada.

   Fetal Alcohol Spectrum Disorder (FASD) is a common and heterogeneous disorder caused by maternal drinking during pregnancy. While much of the research on FASD has focused on behavioural and neuro-structural changes, prenatal alcohol exposure also results in long-term alterations in gene expression; however, the mechanisms underlying the persistence of these changes are not known. In this study, we used four ethanol treatment protocols to model developmental ethanol exposure in mice: injections at 3 specific neurodevelopmental time points that model a binge exposure, and a voluntary maternal consumption model, which represents moderate chronic exposure throughout development. We then assessed small RNA brain gene expression in resulting adult offspring (PD 70) using miRNA expression arrays, mouse gene expression arrays, and quantitative PCR. The analysis revealed that a large number of microRNAs and snoRNAs are altered, both up and down, depending on treatment paradigm. Some of these expression profiles are unique to a treatment protocol while others overlap. Strikingly, approximately 20% of the altered noncoding RNAs (ncRNAs) localized to three imprinted clusters. The first two, Snrpn-Ube3a (Murine 7qC/Human 15q11-q13) and Dlk1-Dio3 (Murine 12qF1/Human 14q32.2), are associated with processes involved in neuronal plasticity and several neurodevelopmental disorders. The third cluster contains Sfmbt2 (Murine 2qA1) and an overlapping antisense transcript that is unique to mice and rats. We then assessed brain DNA methylation using methylated DNA immunoprecipitation followed by hybridization to DNA arrays (MeDIP-Chip), which revealed that fetal alcohol exposure has a genome-wide effect on DNA methylation with imprinted regions of the genome appearing to be particularly sensitive. Ultimately, our results suggest that imprinted ncRNAs, many of which play a critical role in neurodevelopment and brain function, may have a role in the long-term maintenance of altered gene expression and cognitive endophenotypes associated with FASD.

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