Department of Psychiatry, Columbia University, 1051 Riverside Drive, New York, NY 10032, United States.
Brain Behav Immun. 2011 Nov;25(8):1548-53. doi: 10.1016/j.bbi.2011.05.001. Epub 2011 May 11.
Epigenetic marks (e.g., DNA 5-methylcytosine [5mC] content or CpG methylation) within specific gene regulatory regions have been demonstrated to play diverse roles in stress adaptation and resulting health trajectories following early adversity. Yet the developmental programming of the vast majority of the epigenome has not yet been characterized, and its role in the impact of early stress largely unknown. In the present study, we investigated the relationships among early life stress, whole-epigenome and candidate stress pathway gene (serotonin transporter, 5-HTT) methylation patterns, and adult behavioral stress adaptation in a non-human primate model. Early in life, experimental variable foraging demand (VFD) stress or control conditions were administered to two groups each of 10 female bonnet macaques (Macaca radiata) and their mothers. As adults (3-13 years of age), these females were assessed for behavioral adaptation to stress across four conditions of increasing intensity. Blood DNA 5-HTT 5mC status was determined using sodium bisulfite pyrosequencing and total 5mC content was determined using ELISA. Neither stress reactivity nor DNA methylation differed based on early life stress. However, we found that both greater 5-HTT and whole-genome 5mC was associated with enhanced behavioral stress reactivity following early life stress, but not control conditions. Therefore, regardless of developmental origin, greater DNA methylation conferred a genomic background of "risk" in the context of early stress. We suggest that this may arise from constrained plasticity in gene expression needed for stress adaptation early in development. This risk may have wider implications for psychological and physical stress adaptation and health.
表观遗传标记（例如，DNA 5-甲基胞嘧啶[5mC]含量或 CpG 甲基化）在特定基因调控区域内被证明在应激适应和早期逆境后的健康轨迹中发挥着多样化的作用。然而，绝大多数表观基因组的发育编程尚未被描述，其在早期应激影响中的作用也知之甚少。在本研究中，我们在非人灵长类模型中研究了早期生活应激、全表观基因组和候选应激途径基因（5-羟色胺转运体，5-HTT）甲基化模式之间的关系，以及成年行为应激适应。在生命早期，对两组每组 10 只雌性冕狐猴（Macaca radiata）及其母亲进行了实验性可变觅食需求（VFD）应激或对照处理。作为成年人（3-13 岁），这些雌性在四个逐渐增强强度的应激条件下评估了行为应激适应能力。使用亚硫酸氢盐焦磷酸测序法测定血液 5-HTT 5mC 状态，使用 ELISA 测定总 5mC 含量。应激反应或 DNA 甲基化都不因早期生活应激而有所不同。然而，我们发现，无论是在早期生活应激还是对照条件下，5-HTT 和全基因组 5mC 的增加都与增强的行为应激反应相关。因此，无论发育起源如何，更大的 DNA 甲基化赋予了早期应激背景下的“风险”基因组背景。我们认为，这可能源于早期发育中应激适应所需的基因表达的受限可塑性。这种风险可能对心理和身体应激适应和健康产生更广泛的影响。
