Abstract
The neuropeptide oxytocin is involved in the regulation of complex social behaviors. The actions of this neuromodulator are dependent on the oxytocin receptor, which is encoded by the oxytocin receptor gene (OXTR). There is growing interest in examining the relationship between epigenetic programing of OXTR and social behavior in humans. Current studies have focused on DNA methylation at a region within exon 1 and intron 1 (MT2 region) and a segment within exon 3. Of the 22 CpG sites measured across the MT2 region in human brain tissue, only CpGs -934, -924, and -901 had a strong correlation with increases of DNA methylation corresponding to decreases in OXTR expression (-934: ⍴(36) = -0.78, p = 0.006; -924: ⍴(36) = -0.68, p = 0.024; -901: ⍴(36) = -0.65, p = 0.032). Yet, as is common in emerging fields, there is not enough published evidence to draw definitive conclusions on the role of DNA methylation on human social behavior. Therefore, we turned to a commonly used animal model of social behavior, the prairie voles (Microtus ochrogaster) for further analysis. We found that only a small number of CpGs within the conserved MT2 and exon 3 region have a strong inverse relationship between DNA methylation and Oxtr expression. Additionally, to determine if there are environmental drivers of DNA methylation, we investigated the role of parental care in early life. We discovered that the amount of parental care received within the first week of life influences DNA methylation across the conserved MT2 and exon 3 region (2-way ANOVA, p= <0.0001). Following multiple comparison corrections, only 5 CpG sites, all within the conserved MT2 region, had significant differences in DNA methylation. We investigated the relationship between DNA methylation and Oxtr expression of these 5 CpG sites and discovered that only homologous CpGs -934_2, -924, and -901 had a strong trending or significant correlation, with increased Oxtr DNA methylation corresponding to decreases in Oxtr expression (-934_2: ρ(26) = -0.47, p = 0.058; CpG -924: ρ(26) = -0.50, p = 0.043, CpG -901: ρ(26) = -0.47, p = 0.058). Collectively, our findings demonstrate that Oxtr is epigenetically sensitive to early life experience, particularly at CpG sites that are primarily regulating Oxtr expression (-934_2, -924, -901). We show that these CpG sites are homologous in humans, and as we move forward in this emerging field, our findings point to narrowing our region of interest to the homologous CpGs -934, -924, and -901 within the MT2 region in both humans and prairie vole studies.
