Epigenetic Developmental Origins Hypothesis and Oxidative Stress

Epigenetics is a heritable transcriptional regulation mechanism independent of DNA sequence. Epigenetic transcriptional control is achieved by regulation of chromatin conformation. The molecular mechanisms of epigenetics include post-translational modifications of histone and DNA methylation. Histone acetylation is the mostly studied epigenetic regulation. Histone deacetylase (HDAC) deacetylates histones and induce chromatin condensation, which prevent the approach of transcriptional regulating proteins. Methylated DNA is recognized by methyl-CpG binding protein (MBD) which recruits HDAC to the methylated region. Epigenetic status is known to be affected by oxidative stress condition via altering metabolic pathway associated with methylation reaction, and epigenetic abnormality on the developmental stage can influence brain and mental development. These suggest that oxidative stress condition affects brain and mental development via altering epigenetic regulation. In some mental retardation, such as Rett syndrome (RTT) and fetal alcohol syndrome (FAS), patients show microcephaly which may be caused by glial growth abnormality. The responsible gene of RTT is one of the MBDs, MeCP2. We discovered that knock down of MeCP2 in astrocytes reduced the growth rate, and DNA methyltransferase (DNMT) and HDAC inhibitors also did the same. Thus, epigenetic dysregulation induced mental disorder may be, at least partly, caused by abnormality of glial cells.

Keywords: Epigenetic transcriptional control, DNA methylation, histone deacetylase, methyl-CpG binding protein, Rett syndrome, fetal alcohol syndrome