Identification of Epigenetics Correlates between Brain and Peripheral Tissues

摘要 精神障碍，如重度抑郁障碍(MDD)是一种复杂的疾病，在这种疾病中， 应激源通过表观遗传变化增加其发病的可能性，如DNA甲基化(DNaM)。 目前，MDD的疾病相关dNaM模式尚未完全阐明。这在一定程度上是由于 依赖周围组织，如血液、口腔细胞和唾液，其中dNaM如何变化尚不清楚 这些组织可能准确地反映了大脑的这些变化。因此，有一个紧急情况 需要提供一个全面的数据库来交叉比较大脑和大脑之间的dNaM模式 其他周围组织，以突出可观察到与疾病相关的dNaM的候选区域。至 为此，我们的总体目标是建立一个全面的表观基因组数据库，其中dNaM模式可以 大脑关键区域(例如，海马体、杏仁核和额叶背外侧)之间的交叉比较 大脑皮层)、神经元和神经胶质成分以及外周组织。我们的中心假设是疾病- 相关的dNaM更可能存在于不同组织之间dNaM不同的区域。我们的特定 AIMS将解决以下问题：在AIMS 1中，dNaM将在全基因组水平上进行评估，并将在 比较脑组织和周围组织之间的差异，以确定组织之间具有不同dNaM的区域。 在目标2中，我们将把神经元和胶质细胞中的dNaM评估扩展到上述关键的大脑区域 并与周围组织进行比较。在目标3中，与疾病相关的dNaM区域将 使用206例MDD患者和206例匹配对照的病理档案脑组织进行评估。这是 专门评估dNaM的MDD最大尸检研究。与疾病相关的dNaM将是 覆盖特定于组织的dNaM，以确定MDD相关dNaM模式可能 发生。这项拟议的研究具有重要意义，因为它将提供一个全面的表观遗传学数据库，将指导 研究人员到候选区域和合适的外周组织来研究MDD中dNaM的变化。它的用法 也可能延伸到其他精神障碍。这项拟议的研究具有创新性，因为它使用了新鲜的大脑， 从同一个体的神经元、神经胶质细胞和外周组织建立表观基因组数据库。它还使用 从大量死后MDD大脑队列中识别与疾病相关的dNaM，以确定 与疾病相关的甲基化变化的“热点”。

Abstract Psychiatric disorders such as major depressive disorder (MDD) are complex diseases where negative stressors increase the likelihood of its onset through epigenetic changes, such as DNA methylation (DNAm). Presently, disease-associated DNAm patterns of MDD have not been fully elucidated. This is in part due to the reliance of peripheral tissues such as blood, buccal cells, and saliva where it is unknown how DNAm changes from these tissues might be an accurate reflection of those changes in the brain. As such, there is an urgent need to provide a comprehensive database that would cross-compare DNAm patterns between the brain and other peripheral tissues to highlight candidate regions where disease-associated DNAm can be observed. To this end, our overall goal is to establish a comprehensive epigenomic database where DNAm patterns can be cross-compared between key brain regions (e.g., the hippocampus, amygdala, and dorsolateral prefrontal cortex), their neurons and glia components, and peripheral tissues. Our central hypothesis is that disease- associated DNAm will more likely reside in regions that vary in DNAm between different tissues. Our specific aims will address the following questions: In Aim 1, DNAm will be evaluated at a genome-wide level and cross- compared between brain and peripheral tissues to identify regions which have varying DNAm between tissues. In Aim 2, we will expand DNAm assessment in neuron and glia to the aforementioned key brain regions involved in MDD and compare that with peripheral tissues. In Aim 3, disease-associated DNAm regions will be evaluated using pathology-archived brain tissues from 206 MDD cases and 206 matched controls. This is the largest post-mortem study of MDD that specifically evaluates DNAm. Disease-associated DNAm will be overlaid with tissue-specific DNAm to determine regions where MDD-associated DNAm patterns will likely to occur. This proposed study is significant as it will provide a comprehensive epigenetic database that will guide researchers to candidate regions and suitable peripheral tissues to investigate DNAm changes in MDD. Its use may also be extended to other psychiatric disorders. This proposed study is innovative as it uses fresh brain, neuron, glia and peripheral tissues from the same individual to establish an epigenome database. It also uses disease-associated DNAm identified from a large cohort of post-mortem MDD brains to identify regions that are “hot-spots” for disease-associated methylation changes.