Epigenetic effects of fetal alcohol exposure on hypothalamic proopiomelanocortin gene

Rola Aldana Bekdash
2012
Hypothalamic POMC neurons, one of the major regulators of the HPA axis, immune functions, and energy homeostasis, are vulnerable to the adverse effects of fetal alcohol exposure (FAE) exhibiting a significant decrease in POMC gene expression and functions in the arcuate area of the hypothalamus of adult offspring. This permanent deficit in gene expression could be caused by epigenetic mechanisms such as histone modifications and DNA methylation induced by alcohol exposure during critical period
more » ... ing critical period of development. We found that FAE decreased significantly the protein and mRNA levels of histone-modifying enzymes that methylate H3K4me2,3 (Set7/9), acetylate H3K9 (CBP) or phosphorylate H3S10. These are activation marks that correlate with gene expression. FAE significantly increased the protein levels and gene expression of G9a and Setdb1 that methylate the repressive mark H3K9me2 in β-endorphin-producing POMC neurons of adult offspring. These changes were associated with increased levels of the DNA-methyltranferase Dnmt1 and the methyl-CpG-binding protein 2 MeCP2 but not Dnmt3a. Microarray analysis confirmed that alcohol exposure modulated the gene expression profile of the epigenetic machinery in LCM-captured POMC neurons. ChIP assay revealed a significant reduction in the activation mark H3K4me3 along Exon 3 of POMC gene in alcohol-exposed rats associated with no change in the repressive mark H3K9me2 in Exon 3 and promoter region of POMC gene. We then examined whether gestational choline supplementation, a major methyl donor, could mitigate alcohol adverse effects on POMC neurons. Gestational choline normalized in alcohol-exposed rats the methylation of H3K4 and H3K9 with no significant effect on other histone marks such as acetylated H3K9 or phosphorylated H3S10. Similarly, gestational choline normalized the protein levels and gene expression of histone-modifying and DNA-methylating enzymes in POMC neurons. This data correlated with normalization of POMC gene methylation, POMC gene expression and β-EP peptide p [...]
doi:10.7282/t31835jj fatcat:25yjxrjgtvg6hgd5w767ulfmuq