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Monday, April 15, 2013

Long lasting alterations to DNA methylation and ncRNAs may underlie the effects of fetal alcohol exposure

Fetal Alcohol Spectrum Disorders (FASD) 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 report 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 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 qPCR. The results identified 34 genes that are targeted by the deregulated miRNAs. Of these, four (Pten, Nmnat1, Slitrk2, and Otx2) were viewed critical in the context of FASD given their roles in the brain.

Furthermore, ~20% of the altered ncRNAs mapped to three imprinted regions: Snrpn-Ube3a, Dlk1-Dio3, and Sfmbt2, which showed differential methylation and have been previously implicated in neurodevelopmental disorders.

The findings of this report help to expand on the mechanisms behind the long lasting changes in the brain transcriptome of FASD individuals. The observed changes may contribute to the initiation and maintenance of the long lasting effect of alcohol.

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