Fig. 3

The early-life environment modulates the DNA methylation equilibrium; reversibility of DNA methylation. The DNA methylation equilibrium is laid down during embryogenesis by innate developmental programs. Increased methylation of promoters is associated with a hypoacetylated and poorly transcribed gene (right) and hypomethylated promoter is hyperacetylated and highly transcribed (left). A balance of DNA methylation and demethylation activities dynamically maintains this pattern and is attuned to signals from the early environment that can modulate the pattern through activation of signaling pathways that facilitate either increased demethylation or increased methylation. Two examples were previously reported; maternal licking and grooming increases serotonin firing increasing cAMP and activation of protein kinase A, which in turn activates NGFIA facilitating demethylation and histone acetylation of the GR exon 1₇ promoter. Early-life stress triggers activation of CAMKII kinase resulting in phosphorylation of MeCP2 (P). Phosphorylated MeCP2 facilitates demethylation and increased transcription of genes such as AVP. The DNA methylation balance set by early-life environment could be reversed during adulthood using epigenetic modifiers such as the histone deacetylase inhibitor TSA or methionine the precursor of the methyl donor SAM resulting in an epigenetic and behavioral reversal of the phenotype defined by maternal care. (AC histone acetylation, CH ₃ DNA methylation)