Defining the components of olfactory singular expression

定义嗅觉奇异表达的组成部分

• 批准号: 10567951
• 负责人: PAUL FEINSTEIN
• 金额: $ 60.88万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10567951
• 关键词: Address; Afferent Neurons; Alleles; Binding; Binding Sites; Biochemical; Biochemistry; Brain Diseases; Cell Nucleus; Cells; ChIP-seq; Code; Complex; Data; Deposition; Development; Distant; Elements; Enhancers; Epigenetic Process; Exhibits; Experimental Genetics; Gene Cluster; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Diseases; Genetic Transcription; Genome; Greek; Island; Location; Mammals; Messenger RNA; Modeling; Modification; Molecular; Mus; Nature; Nervous System; Nose; Nuclear; Odorant Receptors; Olfactory Pathways; Phenotype; Play; Population; Process; Property; Proteins; Receptor Gene; Role; Scheme; Site; Sucrose; Testing; Time; Transcriptional Activation; Transgenes; Work; cell type; chromatin immunoprecipitation; crosslink; derepression; epigenetic silencing; experimental study; genetic element; histone modification; homeodomain; olfactory nuclei; olfactory sensory neurons; promoter; receptor expression; selective expression; tool; transcription factor

Abstract Monoallelic expression is an unusual form of gene regulation that is often associated with genes that determine cell-type identity. The olfactory system exhibits an intriguing form of random monoallelic expression. Each sensory neuron in the mouse nose expresses only one out of over 2000 odorant receptor (OR) alleles. The current model for OR gene selection involves the interchromosomal aggregation of distributed enhancers into a single active super- enhancer, driven by the co-binding of transcription factors Lhx2 and Ebf. This super-enhancer complex attracts all OR promoters. How this assembly selects a single OR gene promoter for transcription is unknown. Understanding this process requires a better understanding of how OR gene promoters function in the context of this super-enhancer complex. Like OR enhancers, the promoters contain homeodomain (HD) binding sites for Lhx2 and Olf1/Ebf (O/E) binding sites for Ebf transcription factors. How these sites act in OR promoters to engage the choice mechanism is not clear. We propose a set of genetic experiments to define the role of HD and O/E sites in OR promoter function. To do this we will study targeted OR transgenes that lie outside of OR clusters, providing a unique tool to study what genetic and epigenetic features are required for OR expression. Moreover, we propose a combined genetic and biochemical approach to identify the molecular components of the OR choice mechanism in the nucleus. Taken together, these approaches seek to elucidate for the first time the molecular basis for OR monoallelic expression. Our findings will shed light on fundamental mechanisms that govern gene expression in mammals.

抽象的 单等位基因表达是一种不寻常的基因调控形式，通常与 决定细胞类型身份的基因。嗅觉系统表现出一种有趣的形式 随机单等位基因表达。小鼠鼻子中的每个感觉神经元只表达一种 超过 2000 个气味受体 (OR) 等位基因。 OR 基因选择的当前模型 涉及分布式增强子的染色体间聚集成单个活性超级 增强子，由转录因子 Lhx2 和 Ebf 的共同结合驱动。这个超级强化剂 复合物吸引所有 OR 启动子。该组件如何选择单个 OR 基因启动子 转录未知。理解这个过程需要更好地理解如何 OR 基因启动子在该超级增强子复合物的背景下发挥作用。 与 OR 增强子一样，启动子包含 Lhx2 的同源域 (HD) 结合位点 Ebf 转录因子的 Olf1/Ebf (O/E) 结合位点。这些位点如何在 OR 启动子中发挥作用 从事选择机制尚不明确。我们提出了一组基因实验 定义 HD 和 O/E 位点在 OR 启动子功能中的作用。为此，我们将有针对性地研究 OR 转基因位于 OR 簇之外，提供了一种独特的工具来研究遗传和 OR 表达需要表观遗传特征。此外，我们提出了一种组合遗传 和生化方法来识别 OR 选择机制的分子成分 核。总而言之，这些方法试图首次阐明分子 OR 单等位基因表达的基础。我们的研究结果将揭示基本机制 控制哺乳动物基因表达。