Abstract
SUMMARYFetal 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.
Highlights
An epigenetic mechanism brings about changes in gene expression or cellular phenotype through changes other than a change in the underlying DNA sequence
The authors of this report previously generated and characterized mouse models of Fetal alcohol spectrum disorders (FASDs) and observed alterations in post-natal development, adult behavior and gene expression. They sought to determine the mechanisms underlying the long-term alterations in brain gene expression following alcohol exposure during development. They examined the effects of fetal alcohol exposure on the epigenome of adult mice by assaying DNA methylation and non-coding RNA expression
The changes mapped to promoters of small noncoding RNA (ncRNA) molecules that are normally regulated in a parentof-origin manner via epigenetic mechanisms
Summary
An epigenetic mechanism brings about changes in gene expression or cellular phenotype through changes other than a change in the underlying DNA sequence. They are crucial to gene regulation at two distinct levels. The two aforementioned levels of epigenetic regulation are crucial during embryonic development (Howlett and Reik, 1991; Monk et al, 1987), where changes to the epigenome are tightly controlled (Howlett and Reik, 1991; Monk et al, 1987). Alcohol consumption during pregnancy results in the development of fetal alcohol spectrum disorders (FASDs)
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