Olfactory receptor mRNAs as lncRNAs that regulate genomic interactions

嗅觉受体 mRNA 作为调节基因组相互作用的 lncRNA

• 批准号: 10376032
• 负责人: Stavros Lomvardas
• 金额: $ 48.05万
• 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: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10376032
• 关键词: 3-Dimensional; Adaptor Signaling Protein; Affect; Alleles; Architecture; Binding; Binding Proteins; Biochemical; Chromatin; Chromosome Structures; Code; Complex; Data; Development; Developmental Process; Enhancers; Environment; Epigenetic Process; Feedback; Gene Cluster; Gene Expression; Gene Family; Generations; Genetic; Genetic Enhancer Element; Genetic Transcription; Genomics; Greek; Human; In Situ; Island; Light; Link; Mediating; Messenger RNA; Molecular; Mus; Neurodevelopmental Disorder; Neuronal Differentiation; Nuclear; Nuclear Proteins; Olfactory Pathways; Other Genetics; Phase; Phase Transition; Process; Production; Property; Proteins; RNA; RNA-Binding Proteins; Receptor Gene; Regulation; Regulator Genes; Reporting; Repression; Role; Signal Transduction; Specificity; Structure; System; Transcriptional Regulation; Untranslated RNA; Yeasts; experimental study; gene translocation; genetic approach; genomic locus; in vivo; insight; interdisciplinary approach; nerve stem cell; novel; olfactory receptor; olfactory sensory neurons; programs; promoter; receptor expression; recruit; 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 is the process by which an OR allele is recruited to the Greek Island hub and the mechanism that assures that only one OR allele will remain stably associated with a multi-chromosomal structure that contains numerous enhancer elements. Our preliminary data suggest that developmentally transient OR transcription and production of nascent OR mRNAs contribute to the recruitment of an OR allele to the Greek Island hub and to OR gene choice. Thus, we propose genetic experiments that will determine which sequences of the sense OR mRNA are required and sufficient for recruitment of trans OR enhancers, what proteins recognized the nascent OR mRNA and what contribution these proteins have to the assembly of a multi-enhancer/OR complex. These experiments not only will shed light to the enigmatic process of OR gene choice, but will also provide general molecular principles for the mechanisms that mediate genomic compartmentalization during cellular differentiation.

摘要