Mechanisms of epigenetic silencing of olfactory receptor genes

描述（由申请人提供）：嗅觉受体（OR）基因组成了一个约1300个基因的家族，这些基因在小鼠嗅觉上皮中以看似随机的单等位基因方式表达。每个嗅觉感觉神经元只表达一个或基因，这种独特性对于嗅觉系统的正常连接和功能是必不可少的。在这里，我们提供的初步数据表明，一种抑制性表观遗传修饰，组蛋白H3赖氨酸9的三甲基化，可能是所有在感觉神经元中不表达的OR等位基因沉默的原因。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，并将为未来鼻子表观遗传沉默的遗传分析提供目标。

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.