SUMMARY
Fetal alcohol spectrum disorders (FASDs) are characterized by life-long changes in gene expression, neurodevelopment and behavior. What mechanisms initiate and maintain these changes are not known, but current research suggests a role for alcohol-induced epigenetic changes. In this study we assessed alterations to adult mouse brain tissue by assaying DNA cytosine methylation and small noncoding RNA (ncRNA) expression, specifically the microRNA (miRNA) and small nucleolar RNA (snoRNA) subtypes. We found long-lasting alterations in DNA methylation as a result of fetal alcohol exposure, specifically in the imprinted regions of the genome harboring ncRNAs and sequences interacting with regulatory proteins. A large number of major nodes from the identified networks, such as Pten signaling, contained transcriptional repressor CTCF-binding sites in their promoters, illustrating the functional consequences of alcohol-induced changes to DNA methylation. Next, we assessed ncRNA expression using two independent array platforms and quantitative PCR. The results identified 34 genes that are targeted by the deregulated miRNAs. Of these, four (Pten, Nmnat1, Slitrk2 and Otx2) were viewed as being crucial in the context of FASDs given their roles in the brain. Furthermore, ∼20% of the altered ncRNAs mapped to three imprinted regions (Snrpn-Ube3a, Dlk1-Dio3 and Sfmbt2) that showed differential methylation and have been previously implicated in neurodevelopmental disorders. The findings of this study help to expand on the mechanisms behind the long-lasting changes in the brain transcriptome of FASD individuals. The observed changes could contribute to the initiation and maintenance of the long-lasting effect of alcohol.
Footnotes
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COMPETING INTERESTS
The authors declare that they do not have any competing or financial interests.
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AUTHOR CONTRIBUTIONS
This project was developed by B.I.L., M.L.K., K.M., E.J.D. and S.M.S. B.I.L., K.M., M.L.K. and E.J.D. raised the mice, performed the experimental interventions and extracted the RNA. B.I.L. performed the bioinformatic analysis. S.M.F.A., B.I.L. and E.J.D. designed and performed the qPCR experiments. B.I.L., M.L.K. and S.M.S. wrote the manuscript.
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FUNDING
This work was supported by an Ontario Graduate Scholarship (OGS) and Natural Sciences and Engineering Research Council of Canada (NSERC) scholarship to B.I.L., a Queen Elizabeth II Scholarship in Science and Technology (QEIISST) to M.L.K., a scholarship from NSERC to E.J.D., and grants from NSERC, the Canadian Institute of Health Research (CIHR) and the Ontario Mental Health Foundation (OMHF) to S.M.S. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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SUPPLEMENTARY MATERIAL
Supplementary material for this article is available at http://dmm.biologists.org/lookup/suppl/doi:10.1242/dmm.010975/-/DC1
- Received September 28, 2012.
- Accepted April 5, 2013.
- © 2013. Published by The Company of Biologists Ltd
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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