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(NSCs)有望用于神经系统疾病的治疗，了解NSC神经发生和神经胶质形成的分子机制是释放其治疗潜力的关键。NSC的命运是由多个基因的共同作用共同控制的，染色质重塑是一种表观遗传机制，协调多组基因的激活和抑制。这项建议集中在MLL(混合血统白血病)，一种与果蝇三胸相关的染色质重塑因子。三胸组(TrxG)和多梳(PcG)基因产物是进化保守的染色质重塑系统的一部分，该系统分别选择性地维持和沉默基因的表达。PCG成员Bmi1是神经干细胞自我更新所必需的；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，出生后脑室下区(SVZ)中MLL缺陷的NSCs可以存活、增殖并有效地分化为神经胶质细胞；然而，神经元分化严重受损。因此，MLL似乎维持着一个专门指导神经发生而不是胶质发生的转录程序。我们假设MLL在特定神经元谱系的神经发育中是广泛需要的。为了验证这一假设并定义MLL在神经谱系规范中所扮演的角色，我们将利用我们的条件基因敲除小鼠模型追求三个特定的目标。在目标1中，我们将进一步鉴定和表征成年哺乳动物大脑中最大的神经干细胞储存库SVZ的MLL依赖谱系。在目标2中，我们将研究MLL在齿状回颗粒下层(SGL)神经干细胞中的作用，SGL是另一个出生后/成年NSC群体。在目标3中，我们将通过针对更广泛和更早的神经干细胞群体的MLL缺失来发现MLL在胚胎神经发育中所起的作用。总之，来自这些目标的数据为当前和未来的研究奠定了基础，即不同的神经谱系是如何由特定的染色质重塑因子在表观遗传学上“编程”的。 公共卫生相关性： 神经干细胞(NSCs)有望用于神经系统疾病的治疗，了解NSCs分化为神经元和胶质细胞的分子机制是释放其治疗潜力的关键。我们的研究项目旨在确定调控神经干细胞(NSC)自我更新和分化的分子机制。为了让神经干细胞制造神经元，子代细胞需要在表达某些基因的同时抑制其他基因。这种谱系特异性转录程序的维持在一定程度上是由染色质结构调节的--染色质结构是DNA与组蛋白“打包”的状态。我实验室目前的工作表明，MLL染色质重塑因子是神经干细胞分化所必需的；神经胶质分化在没有MLL的情况下正常发生，这表明MLL维持着一种专用于神经发生的转录程序。我们已经开始确定MLL的基因靶点。我们计划同时使用细胞生物学和分子方法来研究MLL如何维持一个特定于神经发生的转录程序。这些信息将显著有助于从用于治疗目的的神经干细胞“编程”特定的神经细胞谱系，例如那些来自胚胎干细胞的神经干细胞。因此，这些拟议研究的数据为在我们的退伍军人群体中开发基于细胞的治疗服务相关伤害以及神经退行性疾病奠定了基础。