Credit: PHOTOALTO

Early-life stress (ELS) has long-lasting effects on the brain, and the epigenetic mechanisms underlying them are beginning to be unravelled. Murgatroyd et al. now show that methyl-CpG-binding protein 2 (MeCP2)-mediated regulation of arginine vasopressin ( Avp ) gene expression in parvocellular hypothalamus neurons contributes to the phenotype induced by maternal separation in mice.

As in previous studies, daily 3-hour separation of mouse pups from their mother persistently altered the offspring's hormonal and behavioural responses to stress; this included elevated Avp mRNA levels in the hypothalamus. Importantly, treatment with an AVP V1b receptor antagonist reversed the mice's increased stress responses and impaired memory, indicating a central role for AVP in the ELS phenotype.

Investigating how ELS might increase hypothalamic Avp expression, the authors found that the Avp enhancer region was persistently hypomethylated at five CpG residues in hypothalamus tissue of ELS mice, and that methylation levels correlated negatively with Avp mRNA levels.

Methylated DNA is targeted by MeCP2, leading to gene silencing; indeed, treating a mouse hypothalamic cell line with a methylation inhibitor reduced MeCP2 binding at the methylation-sensitive enhancer and increased Avp transcription. MeCP2 can be dissociated from methylated DNA through activity-dependent phosphorylation by CAMKII. Accordingly, transfecting the cells with CaMKII or depolarizing them reversed MeCP2-mediated repression of Avp.

Does reduced MeCP2 binding underpin the ELS-induced increase in Avp expression? The authors found that immediately after the end of ELS, MeCP2 phosphorylation was increased and MeCP2 binding to the Avp enhancer was reduced, whereas Avp enhancer methylation levels were unaltered in hypothalamus neurons. By contrast, 6 weeks later, MeCP2 phosphorylation was normalized but key residues of the Avp enhancer were hypomethylated. This suggests that ELS dynamically regulates Avp expression, initially through MeCP2 phosphorylation and later through hypomethylation of the Avp enhancer.

This study shows that phosphorylation and binding of MeCP2 might be a means by which experience drives persistent changes in gene expression, and that Avp is an important target for epigenetic regulation by adverse early-life events.