Figure 8. Model for the formation of early-life stress responsive DNA methylation.

In the undifferentiated state, Tet1 and polycomb complexes (for the sake of simplicity symbolized by the histone methyltransferase Suz12) bind to the Avp enhancer and confer gene silencing. Hereby, Tet1 catalyzes the hydroxylation of methylated CpG residues (mCpG → 5hmC) in favor of further demethylation and maintained polycomb occupancy. Upon hypothalamic-like differentiation, polycomb and Tet1 proteins dissociate and lead to an increase in Avp enhancer methylation. Subsequently, recruitment of Mecp2 together with Hdacs and Dnmts enforces the formation of CpG methylation and repressive histone marks restraining Avp expression. Overall, Avp enhancer methylation does not serve as an ‘on-off switch’ but enables programming of Avp expression in response to early-life stress.