Through unbiased transcriptomics and multiple molecular tools, transient downregulation of the Orthodenticle homeobox 2 (OTX2) gene was recently causatively associated with the development of depressive-like behaviors in a mouse model of early life stress. The analyses presented in this manuscript test the translational applicability of these findings by examining peripheral markers of methylation of OTX2 and OTX2-regulated genes in relation to measures of depression and resting-state functional connectivity data collected as part of a larger study examining risk and resilience in maltreated children. The sample included 157 children between the ages of 8 and 15 years (χ = 11.4, SD = 1.9). DNA specimens were derived from saliva samples and processed using the Illumina 450 K beadchip. A subset of children (N = 47) with DNA specimens also had resting-state functional MRI data. After controlling for demographic factors, cell heterogeneity, and three principal components, maltreatment history and methylation in OTX2 significantly predicted depression in the children. In terms of the imaging data, increased OTX2 methylation was found to be associated with increased functional connectivity between the right vmPFC and bilateral regions of the medial frontal cortex and the cingulate, including the subcallosal gyrus, frontal pole, and paracingulate gyrus-key structures implicated in depression. Mouse models of early stress hold significant promise in helping to unravel the mechanisms by which child adversity confers risk for psychopathology, with data presented in this manuscript supporting a potential role for OTX2 and OTX2-related (e.g., WNT1, PAX6) genes in the pathophysiology of stress-related depressive disorders in children.

中文翻译：

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OTX2 和相关基因的甲基化、虐待和儿童抑郁。

通过无偏转录组学和多种分子工具，Orthodenticle homeobox 2 (OTX2) 基因的瞬时下调最近与早期生活压力小鼠模型中抑郁样行为的发展有因果关系。本手稿中的分析通过检查 OTX2 和 OTX2 调节基因甲基化的外围标志物与抑郁测量和静息状态功能连接数据的测量相关，来测试这些发现的转化适用性，这些数据是作为一项更大的研究的一部分而收集的，该研究是检查风险和恢复力的一部分在受虐待的儿童中。样本包括 157 名 8 至 15 岁的儿童（χ2 = 11.4，SD = 1.9）。DNA 样本来自唾液样本，并使用 Illumina 450 K 珠片进行处理。有 DNA 样本的儿童（N = 47）子集也有静息状态的功能 MRI 数据。在控制人口统计学因素、细胞异质性和三个主要成分后，虐待史和 OTX2 中的甲基化显着预测儿童的抑郁症。在成像数据方面，发现增加的 OTX2 甲基化与右侧 vmPFC 与内侧额叶皮质和扣带回的双侧区域之间的功能连接性增加有关，包括胼胝体下回、额极和牵连的扣带回关键结构在抑郁症中。早期压力的小鼠模型在帮助揭示儿童逆境带来精神病理学风险的机制方面具有重要意义，