Okhovat M, Chen I C, Dehghani Z, Zheng D J, Ikpatt J E, Momoh H, Phelps S M
Section of Integrative Biology, University of Texas at Austin, Austin, TX, USA.
Genes Brain Behav. 2018 Jan;17(1):36-48. doi: 10.1111/gbb.12396. Epub 2017 Jul 6.
Early experiences can have enduring impacts on brain and behavior, but the strength of these effects can be influenced by genetic variation. In principle, polymorphic CpGs (polyCpGs) may contribute to gene-by-environment interactions (G × E) by altering DNA methylation. In this study, we investigate the influence of polyCpGs on the development of vasopressin receptor 1a abundance in the retrosplenial cortex (RSC-V1aR) of prairie voles (Microtus ochrogaster). Two alternative alleles ('HI'/'LO') predict RSC avpr1a expression, V1aR abundance and sexual fidelity in adulthood; these alleles differ in the frequency of CpG sites and in methylation at a putative intron enhancer. We hypothesized that the elevated CpG abundance in the LO allele would make homozygous LO/LO voles more sensitive to developmental perturbations. We found that genotype differences in RSC-V1aR abundance emerged early in ontogeny and were accompanied by differences in methylation of the putative enhancer. As predicted, postnatal treatment with an oxytocin receptor antagonist (OTA) reduced RSC-V1aR abundance in LO/LO adults but not their HI/HI siblings. Similarly, methylation inhibition by zebularine increased RSC-V1aR in LO/LO adults, but not in HI/HI siblings. These data show a gene-by-environment interaction in RSC-V1aR. Surprisingly, however, neither OTA nor zebularine altered adult methylation of the intronic enhancer, suggesting that differences in sensitivity could not be explained by CpG density at the enhancer alone. Methylated DNA immunoprecipiation-sequencing showed additional differentially methylated regions between HI/HI and LO/LO voles. Future research should examine the role of these regions and other regulatory elements in the ontogeny of RSC-V1aR and its developmentally induced changes.
早期经历会对大脑和行为产生持久影响，但这些影响的强度会受到基因变异的影响。原则上，多态性CpG（polyCpGs）可能通过改变DNA甲基化来促成基因与环境的相互作用（G×E）。在本研究中，我们调查了polyCpGs对草原田鼠（Microtus ochrogaster）脾后皮质（RSC-V1aR）中血管升压素受体1a丰度发育的影响。两个替代等位基因（“HI”/“LO”）可预测成年期RSC avpr1a表达、V1aR丰度和性忠诚度；这些等位基因在CpG位点频率和一个假定的内含子增强子的甲基化方面存在差异。我们假设LO等位基因中升高的CpG丰度会使纯合子LO/LO田鼠对发育扰动更敏感。我们发现，RSC-V1aR丰度的基因型差异在个体发育早期就出现了，并且伴随着假定增强子甲基化的差异。如预期的那样，用催产素受体拮抗剂（OTA）进行产后处理会降低LO/LO成年田鼠的RSC-V1aR丰度，但不会降低其HI/HI同胞的丰度。同样，zebularine对甲基化的抑制增加了LO/LO成年田鼠的RSC-V1aR，但对HI/HI同胞没有影响。这些数据显示了RSC-V1aR中基因与环境的相互作用。然而，令人惊讶地是，OTA和zebularine都没有改变内含子增强子的成年甲基化，这表明敏感性差异不能仅由增强子处的CpG密度来解释。甲基化DNA免疫沉淀测序显示HI/HI和田鼠与LO/LO田鼠之间还有其他差异甲基化区域。未来的研究应该检查这些区域和其他调控元件在RSC-V1aR个体发育及其发育诱导变化中的作用。
