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.

摘要 单等位基因表达是一种不寻常的基因调控形式，通常与 决定细胞类型特性的基因。嗅觉系统展示了一种耐人寻味的 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个 在2000多个气味受体(OR)等位基因中。当前的OR基因选择模型 涉及到分布的增强子在染色体间聚集成单一的活性超 增强子，由转录因子LHX2和EBF共同结合驱动。这种超级增强剂 复合体吸引了所有的OR启动子。这个组件是如何选择单个OR基因启动子的 转录情况尚不清楚。要理解这一过程，需要更好地理解 或基因启动子在这种超级增强子复合体的背景下发挥作用。 与OR增强子一样，启动子含有LHX2和LHX2的同源结构域(HD)结合位点 EBF转录因子的Olf1/EBF(O/E)结合位点。这些网站如何在或推广者中发挥作用 参与的选择机制尚不明确。我们提出了一系列基因实验，以 明确HD和O/E位点在OR启动子功能中的作用。为了做到这一点，我们将有针对性地研究 或位于OR簇之外的转基因，为研究哪些基因和 OR的表达需要表观遗传特征。此外，我们还提出了一种组合遗传算法 和生化方法鉴定OR选择机制的分子组成 原子核。综上所述，这些方法试图第一次阐明分子 OR单等位基因表达的基础。我们的发现将阐明基本的机制 它们控制着哺乳动物的基因表达。