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 单相表达是一种不寻常的基因调节形式，通常与 确定细胞类型身份的基因。嗅觉系统表现出一种有趣的形式 随机单行表达。小鼠鼻子中的每个感觉神经元仅表示一个 在2000多个气味受体（OR）等位基因中。当前选择或基因选择的模型 涉及分布式增强剂的染色体互色体聚集到单个活动的超级 - 增强剂，由转录因子LHX2和EBF的共同结合驱动。这个超级增强剂 综合体吸引了所有人或促进者。该组件如何为单个或基因启动子选择 转录未知。了解此过程需要更好地理解 或基因启动子在这个超增强剂复合物的背景下起作用。 喜欢或增强子，启动子包含LHX2和 EBF转录因子的OLF1/EBF（O/E）结合位点。这些站点如何在发起人或发起人中起作用 参与选择机制尚不清楚。我们提出了一组基因实验 定义HD和O/E位点在启动子功能中的作用。为此，我们将研究目标 或在簇外面或簇外的转基因，提供独特的工具来研究哪种遗传和 或表达需要表观遗传特征。此外，我们提出了一个组合的遗传 和生化方法以识别或选择机制的分子成分 核。综上所述，这些方法试图首次阐明分子 基础或单相表达的基础。我们的发现将阐明基本机制 控制哺乳动物中的基因表达。