Epigenetic Mechanisms of Depression in Human Limbic Circuits

人类边缘回路抑郁的表观遗传机制

• 批准号: 9279582
• 负责人: Carol A Tamminga
• 金额: $ 26.06万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9279582
• 关键词: Affect; Anhedonia; Animal Model; Animals; Antidepressive Agents; Autopsy; Behavioral; Biological Markers; Blood; Brain; Brain region; Case Study; Cause of Death; Cell model; ChIP-seq; Characteristics; Chromatin; Clinical; Cognition; Collaborations; Collection; Complement; Data; Data Set; Depressed mood; Diagnostic tests; Dimensions; Employee Strikes; Ensure; Epigenetic Process; Faculty; Female; Fibroblasts; Foundations; Functional disorder; Funding; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Genome; Heterogeneity; Homologous Gene; Human; Individual; Laboratory Animals; Life Experience; Life Stress; Mental Depression; Modeling; Molecular; Molecular Abnormality; Molecular Target; Mus; Neuroglia; Neurons; Nucleosomes; Nucleus Accumbens; Pathway interactions; Patients; Peripheral; Positive Valence; Prefrontal Cortex; Progress Reports; Psychotic Disorders; Recording of previous events; Regulation; Research; Research Domain Criteria; Rodent; Sex Characteristics; Sexual abuse; Social Behavior; Source; Stress; Symptoms; Syndrome; Time; Transcriptional Regulation; Translations; Untranslated RNA; Woman; Work; base; brain tissue; case control; cohort; depression model; emotional abuse; epigenetic regulation; experimental study; gene discovery; genetic risk factor; genome-wide; improved; male; men; molecular pathology; mouse model; novel; physical abuse; sex; social; transcriptome sequencing; transcriptomics

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.

项目摘要 – 项目 4（UT 西南部和西奈山） 在过去四年中，项目 4 在定义基因表达和相关相关方面取得了强劲进展 抑郁症患者大脑边缘特定区域发生的染色质异常。 如图 1 至 3 所示，我们验证了人类抑郁症小鼠模型的大量发现，这确保了 其他项目仍然关注与人类综合症相关的机制，同时，我们定义了新颖的机制。 抑郁人类大脑的转录和表观遗传异常正在完成。 对约 100 名受试者的六个大脑区域进行 RNA 测序——一半为抑郁症，一半为对照；一半为男性，一半为女性。 数据显示，抑郁症男性和抑郁症女性的许多基因受到类似影响，影响性别 也观察到了差异，这表明抑郁症可能是一种根本不同的综合征 该数据集帮助定义了其他项目的当前焦点。 我们将把 RNA-seq 分析扩展到另外 100 个队列。 考虑到抑郁症的异质性，这是必要的，我们将对此进行补充。 与 ChIP-seq 合作，并通过绘制 3D 基因组和核小体周转图与项目 2 和 3 合作，开始 定义全基因组范围内控制人类异常基因表达的表观遗传机制 我们将重点关注这些研究中确定的在特定性别中发生改变的关键靶基因。 人类抑郁症中前额皮质（PFC）或伏隔核（NAc）的调节方式 在小鼠模型中复制的受调控基因包括编码一些长链非编码RNA的基因。 啮齿动物中不存在同源物——强调了人类大脑中基因发现的重要性。 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特征联系起来， 检查早期生活压力的影响并超越抑郁症到行为的关键领域 我们还将继续建立我们的抑郁和控制人类大脑的工作。 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。 抑郁症和其他压力相关疾病的病理生理学机制。