Principles of zonal olfactory receptor gene expression

摘要 > 1000 个嗅觉中的一个的单基因、单等位基因和看似随机的转录选择 在发现最大的哺乳动物基因家族后的几十年里，受体（OR）基因仍然难以捉摸。 然而，在过去的几年里，我们对这种现象的分子基础有了重要的了解。 神秘的基因调控过程。具体来说，我们表明 OR 基因簇在以下位置变得异色： 嗅觉感觉神经元 (OSN) 分化的早期阶段，然后它们聚集在不同的核中 确保其稳定抑制的隔间。由于这种染色体间趋同，基因间 在大多数 OR 基因簇中发现的 OR 增强子（称为希腊群岛）都位于紧密的核中 接近并形成多染色体超级增强子，在每个 OSN 中与转录相关 活性或等位基因。希腊岛屿枢纽的形成取决于适配器的招募 蛋白质 Ldb1，对于希腊群岛之间稳定的染色体间相互作用至关重要 或转录。这种激活和抑制染色体间相互作用的复杂网络一起 通过所选 OR 的表达引发的反馈信号，可能会生成监管框架 对于转录奇异性。然而，尚不清楚这个看似随机的过程是如何发生的。 在与 OSN 沿背腹的空间位置相关的确定性限制下运行 MOE 的顶端-基底轴。这些限制（称为 OR 表达式的区域模式）限制了 每个 OR 基因在五个表达区之一的表达。在这里，我们确定了假定的机制 区带限制，通过揭示仅使 5 区 OR 能够表达的分子机制 区域 5。我们发现 NFI 家族的转录因子能够激活区域 5 OR 的转录激活， 通过介导这些 OR 募集到染色体间 OR 区室。此外，我们表明 抑制性组蛋白修饰 H3K79me3 可能会阻止区外 OR 的表达 NFI 因素的控制。我们提出实验来破译需要哪些 NFI 因素，以及 足以用于 5 区转录程序的规范，以及确定 NFI 如何进行的实验 蛋白质实现了这些区域限制。我们的实验将揭示新的调节机制 核架构，并将揭示发育调节的普遍适用原则 图案化。

Abstract The monogenic, monoallelic, and seemingly stochastic transcriptional choice of one out of > 1000 olfactory receptor (OR) genes remained elusive for decades after the discovery of the largest mammalian gene family. However, in the past few years we obtained significant understanding on the molecular underpinnings of this enigmatic gene regulatory process. Specifically, we showed that OR gene clusters become heterochromatic at the early stages of olfactory sensory neuron (OSN) differentiation and then they aggregate in distinct nuclear compartments that assure their stable repression. As a result of this interchromosomal convergence, intergenic OR enhancers (known as Greek Islands) that are found in most OR gene clusters come in close nuclear proximity and form a multi-chromosomal super-enhancer that in each OSN associates with the transcriptionally active OR allele. The formation of the Greek Island hub is dependent upon the recruitment of the adaptor protein Ldb1, which is essential for the stable interchromosomal interactions between Greek Islands and for OR transcription. This intricate network of activating and repressive interchromosomal interactions, together with a feedback signal elicited by the expression of the chosen OR, likely generate the regulatory framework for transcriptional singularity. However, what remains unknown how this seemingly stochastic process operates under deterministic restrictions related to the spatial location of the OSN along the dorso-ventral and apico-basal axes of the MOE. These restrictions, known as zonal pattern of OR expression, restrict the expression of each OR gene in one of five zones of expression. Here we identified putative mechanisms of zonal restriction, by uncovering the molecular mechanisms that enable only zone 5 ORs to be expressed in zone 5. We show that transcription factors of the NFI family enable the transcriptional activation of zone 5 ORs, by mediating the recruitment of these ORs to the interchromosomal OR compartment. Moreover, we show that the repressive histone modification H3K79me3 prevents the expression of out of zone ORs, possibly under the control of NFI factors, as well. We propose experiments that will decipher which NFI factors are required and sufficient for specification of zone 5 transcription programs, and experiment that will determine how NFI proteins accomplish these zonal restrictions. Our experiments will reveal novel mechanisms of regulation of nuclear architecture, and will uncover generally applicable principles for the regulation of developmental patterning.