Distinct modes of gene expression by KDM5

KDM5 的不同基因表达模式

• 批准号: 10343762
• 负责人: Julie Secombe
• 金额: $ 33.6万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10343762
• 关键词: Address; Adult; Affect; Alleles; Amino Acids; Animal Model; Architecture; Behavioral Assay; Binding; Biological; Biological Assay; Biological Process; Brain; Caregivers; Cells; Cognition; Cognitive; Cognitive deficits; Data; Defect; Development; Disease; Drosophila genus; Etiology; Family; Gene Activation; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Proteins; Genetic; Genetic Transcription; Goals; Growth; Human; Impaired cognition; Individual; Intellectual functioning disability; Knowledge; Lead; Learning; Link; Lysine; Mediating; Memory; Missense Mutation; Molecular; Morphogenesis; Mushroom Bodies; Mutation; Neurodevelopmental Disorder; Neurons; Pathway interactions; Patients; Phenocopy; Phenotype; Physiological; Proteins; Quality of life; RNA Interference; Regulator Genes; Research; Ribosomal Proteins; Role; Testing; Time; Transcriptional Activation; Translations; Work; base; cell type; fly; gene repression; histone demethylase; insight; knock-down; loss of function; mutant; nerve stem cell; neuroblast; neuron development; paralogous gene; prevent; programs; promoter; recruit; therapy development; tool; transcription factor; transcriptome

Abstract Mutations in the lysine demethylase 5 (KDM5) family of transcriptional regulators are found in patients with intellectual disabilities (ID) that show cognitive impairment ranging from mild (IQ 50-70) to severe (IQ < 30). However, the molecular mechanisms by which KDM5 proteins impact neuronal development and function remain unknown, leaving a large knowledge gap and preventing the identification of potential treatments for affected patients. Thus, the long-term goal of our research is to define at the molecular level how KDM5 regulates gene expression patterns necessary for neuronal development and function. We will achieve this using Drosophila because it is an established model organism used to define the molecular basis of human neurodevelopmental disorders. Studies described here use a powerful combination of genetic tools, cell biological analyses and cognitive behavioral assays to dissect KDM5’s gene regulatory activities in neuronal cells at distinct stages of development. In addition to classical loss of function analyses utilizing a newly generated kdm5 null allele and cell type specific inducible RNAi-mediated knockdown assays, we have generated a set of eight fly strains, each of which harbors a mutation in Drosophila kdm5 analogous to a human ID allele. This approach is possible because all disease-associated mutations occur in evolutionarily conserved amino acids. Data generated using these tools lead us to propose the central hypothesis that KDM5 regulates the expression of genes essential for neuronal development and function, and that this is affected by missense mutations associated with intellectual disability. This hypothesis will be tested in three specific aims. The first aim addresses the role of KDM5 in adult brain function by defining the mechanism by which KDM5 activates ribosomal protein (Rp) genes, as de novo translation has an evolutionarily conserved role in learning and memory. The second aim focusses on the role of KDM5 during development by determining the mechanism by which KDM5 functions in larval neuronal stem cells (neuroblasts) to facilitate the subsequent growth and guidance of the neurons required for learning and memory. The third aim defines the temporal and spatial requirements of KDM5 for learning and memory. This work is significant because we will define new mechanisms of gene regulation by KDM5 that are critical for neuronal development and activity in addition to providing insight into the underlying causes of neurodevelopmental disorders.

摘要 转录调节因子赖氨酸脱甲基酶5（KDM 5）家族的突变在患有糖尿病的患者中发现。 智力残疾（ID），表现出轻度（IQ 50-70）至重度（IQ < 30）的认知障碍。 然而，KDM 5蛋白影响神经元发育和功能的分子机制仍然存在， 未知的，留下了很大的知识差距，并阻止确定受影响的潜在治疗方法 患者因此，我们研究的长期目标是在分子水平上确定KDM 5是如何调节基因表达的。 神经元发育和功能所必需的表达模式。我们将用果蝇来实现这一点 因为它是一种已建立的模式生物，用于定义人类神经发育的分子基础， 紊乱这里描述的研究使用了遗传工具、细胞生物学分析和 认知行为分析，以剖析KDM 5的基因调控活动的神经元细胞在不同的阶段， 发展除了利用新产生的kdm 5无效等位基因的经典功能丧失分析外， 细胞类型特异性的可诱导RNAi介导的敲低测定，我们已经产生了一组八个果蝇品系，每个品系 其在果蝇kdm 5中具有类似于人ID等位基因的突变。这种方法是可能的 因为所有与疾病相关的突变都发生在进化上保守的氨基酸中。数据生成使用 这些工具使我们提出了一个中心假设，即KDM 5调节着以下基因的表达： 神经元的发育和功能，这是由与智力相关的错义突变的影响， 残疾。这一假设将在三个具体目标中得到检验。第一个目标是解决KDM 5在成人中的作用。 通过定义KDM 5激活核糖体蛋白（Rp）基因的机制， 翻译在学习和记忆中具有进化上保守的作用。第二个目标是发挥作用 通过确定KDM 5在幼虫神经干中的功能机制， 细胞（神经母细胞），以促进学习所需的神经元的后续生长和指导， 记忆第三个目标定义了KDM 5对学习和记忆的时间和空间要求。这 这项工作意义重大，因为我们将定义KDM 5基因调控的新机制， 神经元发育和活动除了提供对神经元发育和活动的根本原因的深入了解之外， 神经发育障碍