Epigenetic regulation of serotonin transporter expression and behavior in infant rhesus macaques.
Epigenetic regulation of serotonin transporter expression and behavior in infant rhesus macaques.
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DOI：
10.1111/j.1601-183x.2010.00588.x
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发表时间：
2010-08
期刊：
影响因子：
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通讯作者：
Mann JJ
中科院分区：
文献类型：
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作者：
Kinnally EL;Capitanio JP;Leibel R;Deng L;LeDuc C;Haghighi F;Mann JJ
表观遗传机制可能会降低情绪障碍的遗传和环境风险（G × E）。我们使用了一个实验性恒河猴模型的早期生活压力，以测试是否表观遗传调节5-羟色胺转运蛋白（5-HTT）可能有助于G× E的相互作用，影响行为和情绪。我们假设外周血单个核细胞（PBMC）DNA甲基化在一个800 bp的CpG岛内，与5-HTT转录起始位点重叠，这是脑组织中相同基因组区域的一个假设模型，将介导或减轻早期生活应激和功能性5-HTT启动子多态性（rh 5-HTTLPR）对两个结果的影响：PBMC 5-HTT表达和行为应激反应性。87只恒河猴幼崽（3-4个月大）在大型社会群体中由母亲抚养（n= 70）或由托儿所抚养（n= 17）。在母亲/社会分离期间，对婴儿的血液进行采样，并记录行为应激反应。PBMC DNA和RNA样本用于确定：rh 5-HTTLPR基因型;使用qRT-PCR确定5-HTT mRNA表达;使用亚硫酸氢钠焦磷酸测序确定5-HTT CpG甲基化状态。与人类数据一致，低表达rh 5-HTTLPR等位基因的携带者表现出较高的平均5-HTT CpG甲基化，这与PBMC 5-HTT表达较低相关。高5-HTT CpG甲基化，而不是rh 5-HTTLPR基因型，加剧了早期生活应激对婴儿行为应激反应的影响。5-HTT CpG甲基化可能是发育早期5-HTT表达的重要调节因子，并可能导致在“高危“5-HTTLPR携带者中观察到的情绪障碍风险。
Epigenetic mechanisms may moderate genetic and environmental risk (G × E) for mood disorders. We used an experimental rhesus macaque model of early life stress to test whether epigenetic regulation of serotonin transporter (5-HTT) may contribute to G× E interactions that influence behavior and emotion. We hypothesized that peripheral blood mononuclear cell (PBMC) DNA methylation within an 800 bp CpG island that overlaps with the5-HTT transcription initiation start site, a hypothesized model of the same genomic region in brain tissue, would mediate or moderate the effects of early life stress and a functional5-HTT promoter polymorphism (rh5-HTTLPR) on two outcomes: PBMC5-HTT expression; and behavioral stress reactivity. Eighty-seven infant rhesus macaques (3–4 months of age) were either mother-reared in large social groups (n= 70) or nursery-reared (n= 17). During a maternal/social separation, infants’ blood was sampled and behavioral stress reactivity recorded. PBMC DNA and RNA samples were used to determine:rh5-HTTLPR genotype;5-HTT mRNA expression using qRT-PCR; and5-HTT CpG methylation status using sodium bisulfite pyrosequencing. Consistent with human data, carriers of the low expressingrh5-HTTLPR alleles exhibited higher mean5-HTT CpG methylation, which was associated with lower PBMC5-HTT expression. Higher5-HTT CpG methylation, but not rh5-HTTLPR genotype, exacerbated the effects of early life stress on behavioral stress reactivity in infants.5-HTT CpG methylation may be an important regulator of 5-HTT expression early in development, and may contribute to the risk for mood disorders observed in “high-risk”5-HTTLPR carriers.