Principles of zonal olfactory receptor gene expression

带状嗅觉受体基因表达原理

• 批准号: 10570848
• 负责人: Stavros Lomvardas
• 金额: $ 45.88万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570848
• 关键词: Adaptor Signaling Protein; Affect; Alleles; Architecture; Biological; DNA Modification Process; Data; Deposition; Development; Developmental Process; Down-Regulation; Ectopic Expression; Enhancers; Epigenetic Process; Family; Feedback; Gene Cluster; Gene Expression; Gene Family; Genes; Genetic; Genetic Transcription; Genomics; Goals; Greek; In Situ; Individual; Island; Knockout Mice; Location; Mediating; Molecular; NFIA gene; NFIB gene; NFIX gene; Neuronal Differentiation; Nuclear; Olfactory Epithelium; Pattern; Process; Proteins; Receptor Gene; Regulation; Regulator Genes; Regulatory Element; Repression; Role; Running; Signal Transduction; Specific qualifier value; Stochastic Processes; System; Transcription Coactivator; Transcriptional Activation; Transgenic Mice; developmental disease; epigenetic memory; experimental study; histone modification; imprint; insight; nerve stem cell; novel; nuclear factor 1; olfactory receptor; olfactory sensory neurons; prevent; progenitor; programs; promoter; receptor expression; recruit; stem cells; transcription factor

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.

摘要 单基因、单等位基因和看似随机的转录选择&gt；1000嗅觉中的一个 在发现最大的哺乳动物基因家族后，受体(OR)基因几十年来一直难以捉摸。 然而，在过去的几年里，我们对这一现象的分子基础有了重大的理解。 神秘的基因调控过程。具体地说，我们发现OR基因簇在 嗅觉神经元分化的早期阶段，然后聚集在不同的核中 确保他们稳定镇压的隔间。作为这种染色体间收敛的结果，基因间 或在大多数OR基因簇中发现的增强子(称为希腊群岛)出现在紧密的核中 并形成一个多染色体超级增强子，在每个OSN中与转录上的 活动OR等位基因。希腊岛枢纽的形成取决于适配器的招募情况。 蛋白质LDB1，这是希腊群岛和希腊群岛之间稳定的染色体间相互作用所必需的 或者抄写。这个复杂的激活和抑制染色体间相互作用的网络，一起 利用由所选择的OR的表达式引发的反馈信号，可能生成调节框架 因为转录奇点。然而，目前尚不清楚的是，这个看似随机的过程是如何 在与OSN沿背腹方向的空间位置相关的确定性限制下操作 顶端--MOE的基轴。这些限制被称为OR表达式的分区模式，它们限制 每个OR基因在五个表达区域中的一个中的表达。在这里，我们确定了可能的机制 区带限制，通过揭示只使5区ORs在 5区。我们发现NFI家族的转录因子能够使5区ORs转录激活， 通过调节这些OR的募集到染色体间或间隔室。此外，我们证明了 抑制性组蛋白修饰H3K79me3阻止区外ORs的表达，可能是在 NFI因素的控制也是如此。我们提出的实验将破译哪些NFI因素是必需的，以及 足以说明5区转录程序，以及将确定NFI如何 蛋白质完成了这些带状限制。我们的实验将揭示新的调节机制 核架构，并将揭示普遍适用的原则，以规范发展 图案化。