These findings beg the question of how maternal high LG might activate a demethylation of the GR exon 17 promoter. A testable working hypothesis is that high LG leads to activation of NGFIA as a downstream effector of activation of a 5-HT signaling through increase cAMP and PKA. Increased NGFIA increases NGFIA binding to the GR exon 17 promoter. The interaction of NGFIA with the GR exon 17 promoter leads to increased histone acetylation and increased accessibility of the GR exon 17 promoter to demethylase resulting in DNA demethylation. In contrast, in the absence of increased NGFIA during early postnatal life, the 5' CpG site of the NGFIA response element remains methylated and significantly less sensitive to NGFIA over the life span. The methylation of the 5' CpG site is thought to preclude NGFIA binding through the participation of a repressor complex that includes methylated DNA binding proteins and HDACs. This hypothesis predicts that pharmacological activation of chromatin using HDAC inhibitors should result in activation of NGFIA binding and GR exon 17 promoter demethylation. However, the question is whether reversibility
