Mechanisms of Trace Amine-associated Receptor Gene Choice

项目摘要 气味受体(OR)基因表现出一种不寻常的随机单等位基因表达，通常 称为单基因或单基因表达。在小鼠中，嗅觉神经元表达一个等位基因 从散布在基因组中的1,000个基因中提取一个OR基因。当前型号为 或者选择涉及由分布式增强子组成的全基因组网络协调的表观遗传机制。 痕量胺相关受体(TAAR)构成一个小的嗅觉受体基因家族，也是 受制于单数表达。然而，TAAR的表观遗传特性在许多方面不同于ORs 关键方式，让人怀疑两者是否都有共同的单数表达机制。 这项建议的目的是描述TAAR基因单一表达的机制。我们 已经确定了控制TAAR基因表达的局部增强子，并将利用这一知识来测试 关于这些监管要素如何协调选择的假设。该提案的目的是1) 确定增强子功能所需的序列基序，2)阐明其特异性和空间 增强子功能的程度，以及3)表征TAAR基因的三维相互作用图景 集群。这些实验利用TAAR集群的独特方面来测试和扩展当前的模型 单等位基因表达--一种在多种生物过程中起关键作用的现象，包括 剂量补偿、细胞类型规范、表型变异和疾病发病机制。

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.