Mechanisms of Trace Amine-associated Receptor Gene Choice

微量胺相关受体基因选择机制

• 批准号: 10454158
• 负责人: Thomas Bozza
• 金额: $ 56.77万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10454158
• 关键词: 3-Dimensional; Afferent Neurons; Alleles; Amines; Biological Models; Biological Process; Brain; Chromatin; Chromosomes; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; Deletion Mutation; Development; Disease; Dorsal; Dosage Compensation (Genetics); Elements; Enhancers; Environment; Epigenetic Process; Excision; Exhibits; Family; Gene Cluster; Gene Expression; Gene Family; Gene Order; Gene Targeting; Genes; Genetic; Genetic Enhancer Element; Genome; Goals; Knowledge; Light; Mammals; Modeling; Molecular Conformation; Molecular Genetics; Mus; Names; Neurobiology; Neuronal Differentiation; Neurons; Nuclear; Odorant Receptors; Olfactory Epithelium; Olfactory Pathways; Pathogenesis; Phenotype; Play; Population; Probability; Property; Receptor Gene; Repression; Role; Specificity; Testing; Transgenic Organisms; Variant; base; cell type; defined contribution; experimental study; genome-wide; interest; novel; olfactory receptor; olfactory sensory neurons; prevent; promoter; receptor; receptor expression

Project Summary Odorant receptor (OR) genes exhibit an unusual form of random monoallelic expression, commonly referred to as monogenic or singular expression. In the mouse, olfactory sensory neurons express one allele of one OR gene from a large repertoire of >1,000 genes scattered throughout the genome. Current models for OR choice involve epigenetic mechanisms orchestrated by a genome-wide network of distributed enhancers. The Trace Amine Associated Receptors (TAARs) constitute a small olfactory receptor gene family that is also subject to singular expression. However, the epigenetic properties of TAARs differ from ORs in a number of key ways, calling into question whether both share a common mechanism of singular expression. The goal of this proposal is to characterize the mechanisms of singular expression of TAAR genes. We have identified the local enhancers that govern TAAR gene expression and will exploit this knowledge to test hypotheses about how these regulator elements orchestrate choice. The Aims of the proposal are to 1) identify the sequence motifs that are required for enhancer function, 2) elucidate the specificity and spatial extent of enhancer function, and 3) characterize the three-dimensional interaction landscape of the TAAR gene cluster. These experiments exploit unique aspects of the TAAR cluster to test and extend current models of monoallelic expression—a phenomenon that plays a critical role in myriad biological processes including dosage compensation, cell-type specification, phenotypic variation and disease pathogenesis.

项目摘要 气味受体（OR）基因暴露了一种不寻常的随机单相表达，通常 称为单基因或单数表达。在鼠标中，嗅觉感觉神经元表达一个等位基因 来自散布在整个基因组中的> 1,000个基因的大曲目中的一个或基因。当前模型 或选择涉及通过分布式增强剂的全基因组网络精心策划的表观遗传机制。 痕量胺相关受体（TAAR）构成一个小的嗅觉受体基因家族，也是 受奇异表达的约束。但是，TAAR的表观遗传特性与ORS不同 关键方法，质疑两者是否具有奇异表达的共同机制。 该建议的目的是表征TAAR基因的单数表达的机制。我们 已经确定了管理TAAR基因表达的本地增强剂，并将利用此知识进行测试 假设这些调节元素如何编排选择。该提案的目的是1） 确定增强子函数所需的序列基序，2）阐明特异性和空间 增强子函数的范围，3）表征TAAR基因的三维相互作用景观 簇。这些实验利用TAAR群集的独特方面来测试和扩展 单相表达 - 这种现象在众多生物过程中起着至关重要的作用 剂量补偿，细胞类型规范，表型变异和疾病发病机理。