Principles of zonal olfactory receptor gene expression

带状嗅觉受体基因表达原理

• 批准号: 10350605
• 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/10350605
• 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; 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; gene repression; 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.

抽象的 > 1000个嗅觉中的一个单基质，单位型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，几十年来，受体（OR）基因仍然难以捉摸。 但是，在过去的几年中，我们对此分子的基础有了深入的了解 神秘的基因调节过程。具体而言，我们表明或基因簇在 嗅觉感觉神经元（OSN）分化的早期阶段，然后它们在不同的核中聚集 确保其稳定镇压的车厢。由于这种染色体收敛，基因间的 或大多数基因簇中发现的增强剂（称为希腊岛） 接近性并形成一个多染色体超级增强剂，每个OSN与转录相关联 主动或等位基因。希腊岛枢纽的形成取决于适配器的募集 蛋白质LDB1，这对于希腊岛屿和对 或转录。这个复杂的激活和抑制性染色体相互作用的网络一起 通过所选的表达或可能生成调节框架引起的反馈信号 用于转录奇点。但是，尚不清楚这个看似随机的过程 根据与OSN沿着多索 - 腹部的空间位置有关的确定性限制进行操作 教育部的apico-basal轴。这些限制，称为区域模式或表达，限制了 表达或基因在表达的五个区域之一中的表达。在这里，我们确定了假定的机制 划分限制，通过揭示只能在5区中表达的分子机制 第5区。我们表明，NFI家族的转录因子可以使第5区的转录激活， 通过介导这些OR的募集到染色体或隔间。而且，我们表明 抑制性组蛋白修饰H3K79me3可防止外部OR的表达，可能在 也控制NFI因素。我们提出的实验将破译需要哪些NFI因素，并且 足以规定5区的转录程序，并且实验将决定NFI如何 蛋白质完成了这些区域限制。我们的实验将揭示调节的新型机制 核架构，并将发现通常适用于调节发展的原则 图案。