Genetic Studies of Cortex Structure and Development

皮层结构和发育的遗传学研究

• 批准号: 10299476
• 负责人: JOHN L. R. RUBENSTEIN
• 金额: $ 65.05万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10299476
• 关键词: ATAC-seq; Alleles; Automobile Driving; Binding; Biological Assay; Cells; Cerebral cortex; ChIP-seq; Chromatin Remodeling Factor; Code; Development; Diagnosis; Enhancers; Epilepsy; Etiology; Genes; Genetic; Genetic Enhancer Element; Genetic Transcription; Genetic study; Genomics; Hippocampus (Brain); Histone H3; Histones; Human; Human Genetics; Lead; Lysine; Mental deficiency; Mus; Mutation; Neurons; Pattern; Prosencephalon; Regulation; Regulatory Element; Research; Role; Schizophrenia; Signal Transduction; Structure; Testing; Transgenic Mice; Transgenic Organisms; Untranslated RNA; Ventricular; Work; autism spectrum disorder; cell type; conditional mutant; disorder risk; epigenomics; genetic information; genetic variant; human disease; in vivo; insight; neuropsychiatric disorder; novel; progenitor; promoter; spatiotemporal; subventricular zone; transcription factor

PROJECT SUMMARY (30 lines) Dysregulation of cortical development is central to epilepsy, mental deficiency, autism and schizophrenia. Cortical progenitors generate the projection neurons of the cerebral cortex and hippocampus. Understanding the genetic circuitry controlling the development and function of the cortex is essential to interpret human allele variants in people who have neuropsychiatric disorders. To elucidate the genetic circuitry driving the development of cortical progenitors and neurons, we must define the essential transcription factors (TF), regulatory elements (REs) and coding regions. The proposed research on cortical regionalization and laminar specification, will overcome these barriers through the identification and functional characterization of REs implicated in cortical development. Further, the regulation of REs by chromatin modifiers is critical to their appropriate spatiotemporal activity8,9. Here we propose to make inroads into these subjects. We aim to elucidate transcriptional mechanisms through which patterning of cortical progenitors is transmitted to, and maintained in, cortical neurons. In this proposal, we will study TFs and their targets (putative REs or pREs) regulating cortical patterning and lamination (Aim 1). We will profile the regional and laminar epigenomic states of pREs using purified cortical progenitors and differentiating neurons (Aims 2 & 3). We will define the activity and function of pREs using transgenic mice and enhancer deletions (Aim 4). Finally, to define the function of chromatin modifiers in cortical regionalization and lamination, we will study a chromatin modifier conditional mutant (Kdm6b cKO, Aim 5). The proposed studies shift our research from the function of single genes towards understanding how transcriptional networks orchestrate cortical development. We will integrate, our collaborative large-scale genomics analyses of forebrain pREs1,43,44, with our ChIP-Seq (Chromatin Immunoprecipitation-Sequencing) analyses, to identify regional and laminar specific cortical pREs. This information can lead to insights about human disease alleles in non-coding sequences. Moreover, our results will provide critical information about the genetic control of cortical progenitors and neurons. Once integrated with human genetic information, this will lead to insights into how abnormalities in specific gene networks cause human neuropsychiatric disorders; insights that are essential for understanding etiology, diagnosis and perhaps treatment. For instance, mutations in Tbr1 increase autism risk40. Tbr1 encodes a TF that we discovered and functionally characterized2,3,13,38,41,42. We hypothesize that the work proposed herein will identify multiple novel putative REs (pREs), including for Tbr1, that control cortical development, and will be helpful to human geneticists to define the function of non-coding mutations that contribute to disease risk.

项目总结(30行) 皮质发育失调是癫痫、精神缺陷、自闭症和精神分裂症的核心。 皮质祖细胞产生大脑皮层和海马区的投射神经元。理解 控制大脑皮层发育和功能的遗传回路对于解释人类等位基因是必不可少的。 有神经精神障碍的人的变异。为了阐明驱动人类进化的基因电路 对于皮质祖细胞和神经元的发育，我们必须定义必要的转录因子(TF)， 调控元件(RE)和编码区。关于大脑皮层区域化和层流的拟议研究 规范，将通过RE的识别和功能表征来克服这些障碍 与大脑皮层发育有关。此外，染色质修饰物对RES的调节对它们的 适当的时空活动8，9。在这里，我们建议深入研究这些主题。我们的目标是 阐明皮质祖细胞的图案化通过转录机制传递给 维持在大脑皮层神经元中。 在这项提案中，我们将研究转录因子及其调控皮层模式的靶点(假定的RE或PRES 和层压(目标1)。我们将使用纯化的PreS来描述PRES的区域和层流表观状态 皮质祖细胞和分化神经元(目标2和3)。我们将界定PRES的活动和职能 使用转基因小鼠和增强子缺失(目标4)。最后，为了定义染色质修饰物在 皮层区域化和分层，我们将研究一种染色质修饰条件突变体(KDM6B CKO，AIM 5)。 拟议中的研究将我们的研究从单基因的功能转移到了解 转录网络协调大脑皮层发育。我们将整合，我们的大规模合作 用我们的染色质免疫沉淀测序芯片进行前脑pRES1、43、44的基因组学分析 分析，以确定区域和层状特定的皮质PREs。这些信息可以帮助我们深入了解 非编码序列中的人类疾病等位基因。此外，我们的结果将提供有关 皮质祖细胞和神经元的遗传控制。一旦与人类基因信息相结合，这一点 将导致对特定基因网络的异常如何导致人类神经精神疾病的洞察； 对于理解病因、诊断和治疗至关重要的见解。例如, Tbr1基因突变会增加患自闭症的风险。Tbr1编码我们发现的和功能上的Tf 特征为2，3，13，38，41，42。我们假设，这里提出的工作将确定多个新的假定RE (PreS)，包括Tbr1，控制皮质发育，并将有助于人类遗传学家定义 导致疾病风险的非编码突变的功能。