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: 10204129
• 负责人: COREY C HARWELL
• 金额: $ 10.54万
• 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 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10204129
• 关键词: 1p36 deletion syndrome; Axon; 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; 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; Syndrome; Testing; cell type; chromatin modification; conditional knockout; epigenetic regulation; histone methylation; histone modification; innovation; migration; nerve stem cell; neurogenesis; new therapeutic target; progenitor; programs; selective expression; self renewing cell; severe intellectual disability; stem cells; 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神经干细胞，能够自我更新并有序地产生所有皮质神经元细胞类型 顺序时尚。在理解其背后的分子机制方面存在根本差距 神经元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 调节皮质神经发生过程中的细胞命运转变。我们已经确定了转录调节因子 Prdm16（含正调控域 16）是精确调控的关键成分 皮质神经发生过程中定时的细胞命运转变。我们对 Prdm16 的研究作为切入点 了解调节放射状胶质细胞分裂模式的相关遗传和表观遗传程序，以及 其与神经元命运电位的关系。在本提案中，我们计划利用 MARIS（RNA 分析方法） 遵循细胞内分选）定义细胞类型和阶段中 Prdm16 调节的分子程序 具体方式。我们还将确定 PRDM16 结合的时间模式和顺式调节 皮质神经发生过程中的调节元件。我们的研究结果将直接影响 增加我们对早期转录程序和染色质修饰的表达方式的理解 可能导致神经发育障碍。