Alcoholism and fetal alcohol syndrome are the result of the complex interaction of multiple genetic and environmental factors. Recently, it has become apparent that in addition to genetic and environmental factors, epigenetic mechanisms play crucial roles in the etiology of a large number of diseases such as cancer and schizophrenia. Furthermore, developmental abnormalities are known to be associated with aberrant epigenetic changes in DNA and chromatin. Covalent histone modifications and DNA cytosine methylation, particularly in gene promoter regions, are key epigenetic modifications that control chromatin structure and gene expression. Alcohol and its metabolite acetic acid have strong propensity to deregulate methylation donor by inhibiting a key folate-methionine metabolism pathway leading to altered methylation. Thus, fetal development actively engaged in DNA transcription and cell cycling would be a prime target by alcoholinduced epigenetic abnormalities. This proposal will determine if alcohol cause aberrant epigenetic changes in the fetus, and if the alcohol-induced epigenetic abnormalities lead to fetal alcohol syndrome. Our preliminary data indicates that prenatal alcohol exposure causes decreased multiple linker and core histone genes expression, changes histone methylation, and altered gene expression leading to neural specification. In this proposal, we will study alcohol-mediated epigenetic changes in developing embryos. The alcohol exposure level will be carefully controlled, and our analysis will be able to distinguish maternal imprinting from epigenetic effects due to direct alcohol exposure. We will use a C57BL//6J mice whole embryonic culture model, differential methylation hybridization, and novel ChlP-chip technology to determine genome wide epigenetic changes induced by alcohol. Second, we will identify cohort of genes with promoter methylation and transcriptional alterations, confirm the findings using standard RT-PCR / western blot, and determine their functional pathways. Furthermore, the biological significance of the confirmed key genes will be determined using pharmacological inhibitors of DNA methylation and histone acetylation or genetic manipulation, along with phenotypic analysis. The effect of these epigenetic key genes will be confirmed in the in vivo model exposed to alcohol vapor chamber with alcohol exposure pattern and paradigms similar to the whole embryonic culture.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA016698-04
Application #
7681099
Study Section
Special Emphasis Panel (ZAA1-DD (72))
Program Officer
Hereld, Dale
Project Start
2006-09-30
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2011-08-31
Support Year
4
Fiscal Year
2009
Total Cost
$246,323
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Öztürk, Nail Can; Resendiz, Marisol; Öztürk, Hakan et al. (2017) DNA Methylation program in normal and alcohol-induced thinning cortex. Alcohol 60:135-147
Zhou, Feng C; Resendiz, Marisol; Lo, Chiao-Ling et al. (2016) Cell-Wide DNA De-Methylation and Re-Methylation of Purkinje Neurons in the Developing Cerebellum. PLoS One 11:e0162063
Mason, Stephen; Zhou, Feng C (2015) Editorial: Genetics and epigenetics of fetal alcohol spectrum disorders. Front Genet 6:146
Zhou, Feng C (2015) Dissecting FASD through the global transcriptome. Alcohol Clin Exp Res 39:408-12
Resendiz, Marisol; Mason, Stephen; Lo, Chiao-Ling et al. (2014) Epigenetic regulation of the neural transcriptome and alcohol interference during development. Front Genet 5:285
Lossie, Amy C; Muir, William M; Lo, Chiao-Ling et al. (2014) Implications of genomic signatures in the differential vulnerability to fetal alcohol exposure in C57BL/6 and DBA/2 mice. Front Genet 5:173
Lo, Chiao-Ling; Zhou, Feng C (2014) Environmental alterations of epigenetics prior to the birth. Int Rev Neurobiol 115:1-49
Chen, Yuanyuan; Damayanti, Nur P; Irudayaraj, Joseph et al. (2014) Diversity of two forms of DNA methylation in the brain. Front Genet 5:46
Chen, Yuanyuan; Ozturk, Nail Can; Zhou, Feng C (2013) DNA methylation program in developing hippocampus and its alteration by alcohol. PLoS One 8:e60503
Solzak, Jeffrey P; Liang, Yun; Zhou, Feng C et al. (2013) Commonality in Down and fetal alcohol syndromes. Birth Defects Res A Clin Mol Teratol 97:187-97

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