A Neuroepigenomic Model of the Fetal Alcohol Exposure Spectrum. B. I. Laufer, E. J. Diehl, M. L. Kleiber, A. Chokroborty-Hoque, B. Alberry, K. Mantha, S. M. Singh Molecular Genetics Unit, Department of Biology, Western University, London, Ontario, Canada.
Maternal alcohol consumption during pregnancy causes a continuum of heterogeneous disorders termed Fetal Alcohol Spectrum Disorders (FASD). Patients affected with FASD show life long defects, particularly affecting the central nervous system and its complex traits. Our group has developed an animal model using C57BL/6J (B6) mice and genome-wide molecular technologies. The results show that exposure of alcohol during neurodevelopment in B6 mice causes behavioral disabilities matching FASD patients in resulting offspring. Further, the resulting mice show changes in brain gene expression as well as epigenetic marks, including DNA methylation, multiple histone modifications, and ncRNA expression. Interestingly, the genes affected by the epigenetic marks last a lifetime. Also, the genes affected participate in the critical neural processes of apoptosis, neurodevelopment, cellular identity, cell-cell interaction, and signalling. Using genome-wide arrays to interrogate the cytosine methylation and ncRNA expression within the whole brain and hippocampus of adult mice prenatally exposed to alcohol, we have identified an epigenomic footprint that is characterized by alterations to imprinted regions of the genomes, controlled by DNA methylation, that encode multiple developmentally important non-coding RNAs (ncRNAs) and are regulated by CCCTC-binding factor (CTCF), a zinc finger protein. These processes are developmentally integral to the outcome of larger scale cortical brain structure formation, since the events of both pre- and post-natal neurodevelopment are highly dependent on the (epi)genotype as well as the experience and environment of the differentiating cells at the molecular level. Taken together, our models suggest that ethanol can create significant long-term changes to the molecular mechanisms that create and maintain an epigenetic landscape that is essential to normal brain function and future neurodevelopment. The proposed model suggests a potential for effective attenuation of disease endophenotypes, given the plastic nature of the epigenome in response to enriched postnatal environments.
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