Role of MLL Chromatin Remodeling Factor in Neural Stem Cells

MLL 染色质重塑因子在神经干细胞中的作用

• 批准号: 8195891
• 负责人: DANIEL A LIM
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2012-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195891
• 关键词: Adult; Biology; Brain; Cell Culture Techniques; Cell Survival; Cell Therapy; Cell Transplantation; Cells; Cellular biology; Cerebral Ventricles; Characteristics; Chromatin; Chromatin Remodeling Factor; Chromatin Structure; DNA; Data; Defect; Development; Drosophila genus; Embryo; Embryonic Development; Epigenetic Process; Epilepsy; Future; Gene Chips; Gene Expression; Genes; Genetic; Glial Differentiation; Health; Hippocampus (Brain); Histones; Human; In Vitro; Injury; Interneurons; Investigation; Knockout Mice; Life; Maintenance; Medial; Methylation; Modeling; Molecular; Molecular Profiling; Mus; Nature; Neurodegenerative Disorders; Neuroglia; Neuronal Differentiation; Neurons; Oligodendroglia; Phenotype; Play; Polycomb; Population; Production; Proliferating; Proteins; Regulation; Repression; Research Project Grants; Role; Schizophrenia; Services; Stem cells; System; Testing; Therapeutic; Time; Veterans; Work; chromatin immunoprecipitation; chromatin remodeling; daughter cell; dentate gyrus; embryonic stem cell; follow-up; gamma-Aminobutyric Acid; gliogenesis; immunocytochemistry; in vivo; leukemia; member; mouse model; nerve stem cell; nervous system disorder; neuroblast; neurodevelopment; neurogenesis; olfactory bulb; overexpression; postnatal; programs; relating to nervous system; repository; research study; self-renewal; stem cell differentiation; stem cell fate; stem cell population; subventricular zone; transcription factor

DESCRIPTION (provided by applicant): Neural stem cells (NSCs) hold promise for the treatment of neurological disorders, and understanding the molecular mechanisms of NSC neurogenesis and gliogenesis is key to unlocking their therapeutic potential. NSC fate is controlled by the collective action of many genes expressed in parallel, and chromatin remodeling is an epigenetic mechanism that coordinates the activation and repression of sets of genes. This proposal focuses on Mll (Mixed lineage leukemia), a chromatin remodeling factor related to Drosophila Trithorax. The trithorax group (trxG) and Polycomb (PcG) gene products are part of an evolutionarily conserved chromatin remodeling system that selectively maintain and silence gene expression, respectively. PcG member Bmi1 is required for NSC self-renewal; roles for trxG member Mll in neural development are unknown. Our Preliminary Studies indicate that Mll-deficient NSCs in the postnatal brain subventricular zone (SVZ) can survive, proliferate, and efficiently differentiate into glial lineages; however, neuronal differentiation is severely impaired. Thus, Mll appears to maintain a transcriptional program that specifically instructs neurogenesis and not gliogenesis. We hypothesize that Mll is broadly required in neural development for specific neuronal lineages. To test this hypothesis and to define the roles that Mll plays in neural lineage specification, we will pursue three specific aims utilizing our conditional knockout mouse model. In Aim 1, we will further identify and characterize the Mll-dependent lineages from the SVZ, the largest repository of NSCs in the adult mammalian brain. In Aim 2, we will investigate the role that Mll plays in the NSCs of the dentate gyrus subgranular layer (SGL), the other postnatal/adult NSC population. In Aim 3, we will discover the roles that Mll plays in embryonic neural development by targeting Mll deletion to a broader and earlier population of NSCs. Together, data from these Aims lay the groundwork for current and future investigations of how distinct neural lineages are epigenetically "programmed" by specific chromatin remodeling factors. PUBLIC HEALTH RELEVANCE: Neural stem cells (NSCs) hold promise for the treatment of neurological disorders, and understanding the molecular mechanisms by which NSCs differentiate into neurons and glia is key to unlocking their therapeutic potential. Our research projects are aimed at determining the molecular mechanisms that regulate neural stem cell (NSC) self-renewal and differentiation. For NSCs to make neurons, daughter cells need to express certain sets of genes while repressing others. The maintenance of such lineage-specific transcriptional programs is in part regulated by chromatin structure - the "packaged" state of DNA with histone proteins. Current work in my lab demonstrates that the MLL chromatin remodeling factor is required for neuronal differentiation from NSCs; glial differentiation occurs normally without MLL, suggesting that MLL maintains a transcriptional program specific for neurogenesis. We have begun to identify the genetic targets of MLL. We plan to use both cell biology and molecular approaches to investigate how MLL maintains a transcriptional program specific for neurogenesis. Such information will contribute prominently to the efforts to "program" specific neuronal lineages from NSCs intended for therapeutic purposes, such as those derived from embryonic stem cells. Thus data from these proposed studies lay the groundwork for the development of cell-based therapies for both service-related injuries as well as neurodegenerative diseases in our veteran population.

描述（由申请人提供）： 神经干细胞（NSC）有望治疗神经系统疾病，了解NSC神经发生和神经胶质发生的分子机制是释放其治疗潜力的关键。 NSC命运受许多并行表达的基因的集体作用控制，染色质重塑是一种表观遗传机制，可协调基因组的激活和抑制。该提案的重点是MLL（混合谱系白血病），这是一种与果蝇三脂有关的染色质重塑因子。 Trithorax组（TRXG）和PolyComb（PCG）基因产物是进化保守的染色质重塑系统的一部分，分别有选择地维持和沉默基因表达。 NSC自我更新需要PCG成员BMI1； TRXG成员MLL在神经发育中的作用尚不清楚。我们的初步研究表明，产后脑室内室内区（SVZ）中的MLL缺陷NSC可以生存，增殖和有效地分化为神经胶质谱系。但是，神经元分化受到严重损害。因此，MLL似乎维持了一个专门指导神经发生而不是神经胶质发生的转录程序。我们假设在特定神经元谱系的神经发育中，MLL广泛必不可少。为了检验这一假设并定义了MLL在神经谱系规范中的作用，我们将利用条件敲除小鼠模型实现三个特定目标。在AIM 1中，我们将进一步识别和表征来自成年哺乳动物大脑中NSC最大的SVZ的MLL依赖性谱系。在AIM 2中，我们将研究MLL在齿状回的NSC（SGL）（SGL）的NSC中所起的作用，该层（SGL）是其他后/成人NSC种群。在AIM 3中，我们将通过将MLL缺失靶向更广泛，更早的NSC人群，从而发现MLL在胚胎神经发育中所起的作用。总之，这些目标的数据为当前和将来的研究奠定了基础，即如何通过特定的染色质重塑因子表观遗传“编程”了不同的神经谱系。 公共卫生相关性： 神经干细胞（NSC）有望治疗神经系统疾病，并了解NSC分化为神经元的分子机制，而神经胶质是释放其治疗潜力的关键。我们的研究项目旨在确定调节神经干细胞（NSC）自我更新和分化的分子机制。为了使NSC制作神经元，子细胞需要表达某些基因，同时抑制他人。这种谱系特异性转录程序的维护部分受染色质结构调节 - 与组蛋白的“包装” DNA状态。我实验室中的当前工作表明，与NSC的神经元分化需要MLL染色质重塑因子。神经胶质分化通常没有MLL，这表明MLL维持特定于神经发生的转录程序。我们已经开始确定MLL的遗传靶标。我们计划使用细胞生物学和分子方法来研究MLL如何保持针对神经发生的转录程序。此类信息将有助于从旨在治疗目的的NSC中“编程”特定的神经元谱系的努力，例如源自胚胎干细胞的神经元。因此，来自这些拟议研究的数据为我们退伍军人人群中与服务相关的损伤以及神经退行性疾病的开发开发了基础。