Epigenetic Mechanisms of Depression in Human Limbic Circuits

项目概要-项目4（UT西南和西奈山） 在过去的四年里，项目4在定义基因表达和相关基因表达方面取得了巨大进展。 在抑郁症患者的特定边缘脑区发生的染色质异常。使用项目 1到3，我们验证了人类抑郁症小鼠模型的许多发现，这确保了 其他项目仍然侧重于与人类综合症有关的机制。与此同时，我们定义了小说 转录和表观遗传异常在抑郁的人类大脑。一个重要的里程碑正在完成 来自100名受试者的六个大脑区域的RNA-seq-一半抑郁，一半控制;一半男性，一半女性。而 数据显示，许多基因在抑郁的男性和女性中受到类似的影响， 差异也被观察到，这表明抑郁症可能是一个根本不同的综合征， 两种性别。该数据集有助于确定其他项目的当前重点。又提供了 我们提出的实验的基础。我们将把RNA-seq分析扩展到另外100个队列， 受试者，这是必要的，因为抑郁症的异质性。我们将补充这一点 我与ChIP-seq合作，并与项目2和项目3合作，通过绘制3D基因组和核小体周转图，开始 在全基因组范围内定义控制人类中异常基因表达的表观遗传机制， 萧条我们将重点关注在这些研究中确定的关键靶基因，这些基因在性别特异性基因表达中被改变。 在人类抑郁症中，前额叶皮层（PFC）或脑桥核（NAc）的调节方式， 在小鼠模型中复制。在这些受调控的基因中，有一些编码长链非编码RNA 在啮齿类动物中不存在这种基因的同源物--强调了在人类大脑中发现基因的重要性。 同样，我们将把基因和染色质的变化与病例和对照组的人口统计学特征联系起来， 研究早期生活压力的影响，并超越综合征抑郁症的关键领域， 异常我们还将继续建立我们的抑郁症和控制人类大脑的银行。的工作 因此，项目4体现了双向翻译，定义了这个中心及其发现新的 抑郁症和其他压力相关疾病的病理生理机制。

PROJECT SUMMARY – PROJECT 4 (UT SOUTHWESTERN AND MOUNT SINAI) Over the past four years, Project 4 has made robust progress in defining gene expression and associated chromatin abnormalities that occur in specific limbic brain regions of depressed humans. Working with Projects 1 through 3, we validated numerous findings from mouse models in human depression, which ensures that the other Projects remain focused on mechanisms relevant to the human syndrome. In parallel, we defined novel transcriptional and epigenetic abnormalities in the depressed human brain. A major milestone is completing RNA-seq of six brain regions from ~100 subjects—half depressed, half control; half male, half female. While the data revealed many genes similarly affected in depressed men and depressed women, striking sex differences were observed as well, suggesting that depression may be a fundamentally distinct syndrome in the two sexes. This dataset helped define the current focus of the other Projects. It also provides the foundation for our proposed experiments. We will extend RNA-seq analysis to an additional cohort of 100 subjects, which is necessary given the heterogeneity of the depression syndrome. We will complement this work with ChIP-seq and, with Projects 2 and 3 by mapping the 3D genome and nucleosome turnover, to begin to define genome-wide the epigenetic mechanisms controlling the aberrant gene expression seen in human depression. We will focus on key target genes identified in these studies as being altered in a sex-specific manner in either prefrontal cortex (PFC) or nucleus accumbens (NAc) in human depression, regulation since replicated in mouse models. Among the regulated genes are those that encode several long-noncoding RNAs for which homologues do not exist in rodents—emphasizing the importance of gene discovery in human brain. As well, we will relate gene and chromatin changes to demographic features of the cases and controls, examining the effect of early life stress and moving beyond syndromal depression to key domains of behavioral abnormalities. We also will continue to build our bank of depressed and control human brains. The work of Project 4 thus embodies the bidirectional translation that defines this Center and its promise of discovering new mechanisms for the pathophysiology of depression and other stress-related illnesses.