Long-lasting alterations to DNA methylation and ncRNAs could underlie the effects of fetal alcohol exposure in mice

Autor: Shiva M. Singh, Eric J. Diehl, Sean M. F. Addison, Morgan L. Kleiber, Katarzyna Mantha, Benjamin I. Laufer
Rok vydání: 2013
Předmět:
Male
Aging
CCCTC-Binding Factor
RNA
Untranslated
Time Factors
Medicine (miscellaneous)
lcsh:Medicine
Epigenesis
Genetic
Transcriptome
Mice
0302 clinical medicine
Immunology and Microbiology (miscellaneous)
Pregnancy
Gene expression
Cluster Analysis
Gene Regulatory Networks
Small nucleolar RNA
Promoter Regions
Genetic
Genetics
0303 health sciences
Genome
Brain
Gene Expression Regulation
Developmental
Non-coding RNA
Fetal Alcohol Spectrum Disorders
Maternal Exposure
DNA methylation
Female
lcsh:RB1-214
Protein Binding
Research Article
Neuroscience (miscellaneous)
Biology
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
microRNA
lcsh:Pathology
Animals
Epigenetics
Gene
030304 developmental biology
Binding Sites
Models
Genetic
lcsh:R
Computational Biology
Reproducibility of Results
DNA Methylation
Repressor Proteins
MicroRNAs
030217 neurology & neurosurgery
Zdroj: Disease Models & Mechanisms
Disease Models & Mechanisms, Vol 6, Iss 4, Pp 977-992 (2013)
ISSN: 1754-8411
Popis: 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.
Databáze: OpenAIRE
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