Epigenetic Regulation of Cortical Neuronal Lineage Progression

皮质神经元谱系进展的表观遗传调控

• 批准号: 9362098
• 负责人: COREY C HARWELL
• 金额: $ 38.54万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9362098
• 关键词: 1p36 deletion syndrome; Alpha Cell; Binding; Brain; CRISPR/Cas technology; Cell division; Cells; Cerebral cortex; ChIP-seq; Competence; Data; Development; Disease; Ensure; Epigenetic Process; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Growth; Human; Intellectual functioning disability; Knock-out; Lead; Link; Methodology; Methods; Methylation; Methyltransferase; Molecular; Mutate; Mutation; Neurodevelopmental Disorder; Neuroglia; Neurologic Symptoms; Neurons; Pattern; Phase; Process; Production; RNA analysis; Radial; Regulation; Regulatory Element; Role; Sorting - Cell Movement; Specific qualifier value; Stem cells; Syndrome; Testing; cell type; chromatin modification; epigenetic regulation; histone methylation; histone modification; innovation; migration; nerve stem cell; neurogenesis; new therapeutic target; progenitor; programs; selective expression; self renewing cell; treatment strategy

Cortical radial glia are neural stem cells that self renew and produce all cortical neuron cell types in an orderly sequential fashion. There is a fundamental gap in understanding the molecular mechanism that underlies the orderly production of neuronal cell types. Our overall goal is to understand the intrinsic timing mechanism that regulates cell fate transitions during cortical neurogenesis. We have identified the transcriptional regulator Prdm16 (Positive Regulatory Domain-containing 16) as being a critical component for regulating precisely timed cell fate transitions during cortical neurogenesis. Our studies of Prdm16 serve as an entry point to understanding the relevant genetic and epigenetic programs regulating the mode of radial glia cell division, and its relationship to neuronal fate potential. In this proposal we plan to utilize MARIS (Method for Analyzing RNA following Intracellular Sorting) to define the molecular programs regulated by Prdm16 in a cell type and stage specific manner. We will also determine the temporal pattern of PRDM16 binding and regulation of cis- regulatory elements during cortical neurogenesis. The finding from our studies will have a direct impact on increasing our understanding of how expression of early transcriptional programs and chromatin modifications can contribute to neurodevelopmental disorders.

皮质放射状胶质细胞是一种神经干细胞，能够自我更新并有序地产生所有类型的皮质神经细胞。 循序渐进的时尚。在理解作为基础的分子机制方面存在着根本性的差距 神经细胞类型的有序产生。我们的总体目标是了解内在的计时机制 调节大脑皮层神经发生过程中细胞命运的转变。我们已经确定了转录调控因子 PRDM16(含正调控结构域16)是精确调控的关键成分 皮质神经发生过程中细胞命运的计时转变。我们对Prdm16的研究是一个切入点 了解调节放射状胶质细胞分裂方式的相关遗传和表观遗传程序，以及 它与神经元命运潜能的关系。在这个提案中，我们计划使用Maris(分析RNA的方法 在细胞内分选之后)以定义在细胞类型和阶段中由Prdm16调节的分子程序 具体的方式。我们还将确定PRDM16结合的时间模式和顺式- 大脑皮层神经发生过程中的调控因素。我们的研究结果将对 增加我们对早期转录程序和染色质修饰的表达的理解 会导致神经发育障碍。