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.

摘要 > 1000个嗅觉基因中的一个的单基因、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，我们对这一分子基础有了重要的了解。 神秘的基因调控过程具体地说，我们发现OR基因簇在2000 - 2005年成为异染色质。 嗅感觉神经元（OSN）分化的早期阶段，然后它们聚集在不同的核 确保其稳定抑制的隔室。由于这种染色体间的聚合，基因间 在大多数OR基因簇中发现的OR增强子（称为希腊岛）与细胞核紧密相连， 邻近并形成多染色体超级增强子，其在每个OSN中与转录相关。 活动OR等位基因。希腊岛枢纽的形成取决于适配器的招募 蛋白Ldb 1，这是必不可少的稳定染色体间的相互作用，希腊群岛和 或转录。这种复杂的激活和抑制染色体间相互作用的网络， 通过选择OR的表达引发的反馈信号，可能产生调节框架 转录奇异性。然而，这个看似随机的过程 在与OSN沿背腹沿着的空间位置相关的确定性限制下操作， 莫伊的顶基轴。这些限制被称为OR表达的区域模式， 每个OR基因在五个表达区之一的表达。在这里，我们确定了 区域限制，通过揭示分子机制，使只有5区OR表达， 5区。我们发现NFI家族的转录因子能够激活5区OR的转录， 通过介导这些OR向染色体间OR区室的募集。此外，我们表明， 抑制性组蛋白修饰H3 K79 me 3阻止了区带外OR的表达，这可能是在 控制NFI因素。我们提出的实验，将破译哪些NFI因素是必需的， 足以规范区5转录程序，实验将确定如何NFI 蛋白质完成这些区域限制。我们的实验将揭示新的调节机制， 核架构，并将揭示普遍适用的原则，为发展的监管 模式化