Genetic, epigenetic, and environmental factors controlling oxytocin receptor gene expression

<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>The neuropeptide oxytocin regulates mammalian social behavior. Disruptions in oxytocin signaling are a feature of many psychopathologies. One commonly studied biomarker for oxytocin involvement in psychiatric diseases is DNA methylation at the oxytocin receptor gene (<jats:italic>OXTR</jats:italic>). Such studies focus on DNA methylation in two regions of <jats:italic>OXTR</jats:italic>, exon 3 and a region termed MT2 which overlaps exon 1 and intron 1. However, the relative contribution of exon 3 and MT2 in regulating <jats:italic>OXTR</jats:italic> gene expression in the brain is currently unknown.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>Here, we use the prairie vole as a translational animal model to investigate genetic, epigenetic, and environmental factors affecting <jats:italic>Oxtr</jats:italic> gene expression in a region of the brain that has been shown to drive <jats:italic>Oxtr</jats:italic> related behavior in the vole, the nucleus accumbens. We show that the genetic structure of <jats:italic>Oxtr</jats:italic> in prairie voles resembles human <jats:italic>OXTR</jats:italic>. We then studied the effects of early life experience on DNA methylation in two regions of a CpG island surrounding the <jats:italic>Oxtr</jats:italic> promoter: MT2 and exon 3. We show that early nurture in the form of parental care results in DNA hypomethylation of <jats:italic>Oxtr</jats:italic> in both MT2 and exon 3, but only DNA methylation in MT2 is associated with <jats:italic>Oxtr</jats:italic> gene expression. Network analyses indicate that CpG sites in the 3′ portion of MT2 are most highly associated with <jats:italic>Oxtr</jats:italic> gene expression. We also identify two novel SNPs in exon 3 of <jats:italic>Oxtr</jats:italic> in prairie voles and a novel alternative transcript originating from the third intron of the gene. Expression of the novel alternative transcript is associated with genotype at SNP KLW2.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>These results identify putative regulatory features of <jats:italic>Oxtr</jats:italic> in prairie voles which inform future studies examining <jats:italic>OXTR</jats:italic> in human social behaviors and disorders. These studies indicate that in prairie voles, DNA methylation in MT2, particularly in the 3′ portion, is more predictive of <jats:italic>Oxtr</jats:italic> gene expression than DNA methylation in exon 3. Similarly, in human temporal cortex, we find that DNA methylation in the 3′ portion of MT2 is associated with <jats:italic>OXTR</jats:italic> expression. Together, these results suggest that among the CpG sites studied, DNA methylation of MT2 may be the most reliable indicator of <jats:italic>OXTR</jats:italic> gene expression. We also identify novel features of prairie vole <jats:italic>Oxtr</jats:italic>, including SNPs and an alternative transcript, which further develop the prairie vole as a translational model for studies of <jats:italic>OXTR</jats:italic>.</jats:p> </jats:sec>