Early rearing history influences oxytocin receptor epigenetic regulation in rhesus macaques

Significance

Epigenetically programmed stress adaptation may be a conduit for informing offspring of environmental challenge. We employed ChIP-sequencing to examine effects of early environment on epigenetic regulation using hippocampal samples from macaques exposed to disruption in maternal care. We found decreased H3K4me3 binding at genes critical to behavioral stress response, the most robust being the oxytocin receptor gene ( OXTR), for which we observed a corresponding decrease in RNA expression. Post hoc analysis showed that a gain-of-function OXTR SNP rescued behavioral differences in early stress-exposed subjects. Our data suggest that epigenetic down-modulation of OXTR in brain could contribute to behavioral differences observed in early stress-exposed subjects and that functional genetic variation plays a role. These could have translational implications for human psychiatric disease and personality disorders.

Abstract

Adaptations to stress can occur through epigenetic processes and may be a conduit for informing offspring of environmental challenge. We employed ChIP-sequencing for H3K4me3 to examine effects of early maternal deprivation (peer-rearing, PR) in archived rhesus macaque hippocampal samples (male, n = 13). Focusing on genes with roles in stress response and behavior, we assessed the effects of rearing on H3K4me3 binding by ANOVA. We found decreased H3K4me3 binding at genes critical to behavioral stress response, the most robust being the oxytocin receptor gene OXTR, for which we observed a corresponding decrease in RNA expression. Based on this finding, we performed behavioral analyses to determine whether a gain-of-function nonsynonymous OXTR SNP interacted with early stress to influence relevant behavioral stress reactivity phenotypes ( n = 194), revealing that this SNP partially rescued the PR phenotype. PR infants exhibited higher levels of separation anxiety and arousal in response to social separation, but infants carrying the alternative OXTR allele did not exhibit as great a separation response. These data indicate that the oxytocin system is involved in social-separation response and suggest that epigenetic down-modulation of OXTR could contribute to behavioral differences observed in PR animals. Epigenetic changes at OXTR may represent predictive adaptive responses that could impart readiness to respond to environmental challenge or maintain proximity to a caregiver but also contribute to behavioral pathology. Our data also demonstrate that OXTR polymorphism can permit animals to partially overcome the detrimental effects of early maternal deprivation, which could have translational implications for human psychiatric disorders.