Epigenetic Mechanisms of Depression in Human Limbic Circuits

项目总结--项目4(德克萨斯州西南部和西奈山) 在过去的四年里，项目4在定义基因表达和相关的 出现在抑郁症患者特定边缘脑区的染色质异常。使用项目 1到3，我们验证了人类抑郁症小鼠模型的大量发现，这确保了 其他项目仍然侧重于与人类综合症相关的机制。同时，我们定义了小说 抑郁人脑中的转录和表观遗传学异常。一个重要的里程碑正在完成 来自大约100名受试者的六个大脑区域的RNA序列--一半是抑郁症，一半是对照组；一半是男性，一半是女性。而当 数据显示，在抑郁的男性和抑郁的女性中，许多基因受到类似的影响，与性别有关 也观察到了差异，这表明抑郁症可能是一种从根本上不同的综合征 两个性别。该数据集帮助定义了其他项目的当前重点。它还提供了 为我们提议的实验奠定了基础。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，因为抑郁症综合征的异质性。我们将补充这一点 与CHIP-SEQ合作，并通过绘制3D基因组和核小体周转来开始项目2和3 确定全基因组范围内控制人类异常基因表达的表观遗传学机制 抑郁症。我们将把重点放在这些研究中发现的性别特异性改变的关键靶基因上。 人类抑郁症前额叶皮质(PFC)或伏隔核(NAC)的调节方式 在小鼠模型中复制。在受调控的基因中，有一些编码几个长非编码RNA的基因 为此，啮齿动物中不存在同源基因--强调了在人类大脑中发现基因的重要性。 此外，我们还将把基因和染色质的变化与病例和对照的人口统计学特征联系起来， 研究早期生活应激和超越综合症抑郁对行为关键领域的影响 异常现象。我们还将继续建立我们的抑郁银行，并控制人类的大脑。的工作 因此，项目4体现了定义该中心的双向翻译及其发现新事物的承诺 抑郁症和其他应激相关疾病的病理生理学机制。

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.