Mechanisms of epigenetic silencing of olfactory receptor genes

描述(申请人提供)：嗅觉受体(OR)基因组成一个约1,300个基因家族，在小鼠嗅觉上皮细胞中以随机和单等位基因的方式表达。每个嗅觉神经元只表达一个OR基因，这种奇异性对于嗅觉系统的正确连接和功能是必不可少的。在这里，我们提供了初步的数据，抑制性的表观遗传修饰，组蛋白H3的赖氨酸9的三甲基化，可能导致所有不在感觉神经元中表达的OR等位基因的沉默。我们提出的实验将监测嗅觉上皮中这种修饰的空间和时间坐标，并将揭示协调它的分子成分。这些实验对于理解这种抑制机制在OR选择中的作用至关重要，并将为未来鼻部表观遗传沉默的遗传分析提供靶点。 公共卫生相关性：这项建议旨在分析嗅觉受体基因在嗅觉上皮细胞发育过程中的表观遗传沉默。嗅觉是人类最原始的感觉，了解嗅觉受体基因的表观遗传调控将揭示哺乳动物神经元多样性和功能产生的原理。

DESCRIPTION (provided by applicant): Olfactory receptor (OR) genes compose a family of ~1,300 genes that are expressed in a, seemingly, stochastic and monoallelic fashion in the mouse olfactory epithelium. Each olfactory sensory neuron expresses only one OR gene from the whole repertoire and this singularity is essential for the proper wiring and function of the olfactory system. Here, we present preliminary data that a repressive epigenetic modification, trimethylation of lysine 9 of histone H3, may be responsible for the silencing of all the OR alleles that are not expressed in a sensory neuron. We propose experiments that will monitor the spatial and temporal coordinates of this modification in the olfactory epithelium and will reveal the molecular components that orchestrate it. These experiments are essential for understanding the role of this repressive mechanism in OR choice and will provide targets for future genetic analyses of epigenetic silencing in the nose. PUBLIC HEALTH RELEVANCE: This proposal aims to analyze the epigenetic silencing of olfactory receptor genes during the development of the olfactory epithelium. Olfaction is a primal human sense and understanding the epigenetic regulation of olfactory receptor genes will uncover principles for the generation of mammalian neuronal diversity and function.