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
基本信息
- 批准号:10376032
- 负责人:
- 金额:$ 48.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:3-DimensionalAdaptor Signaling ProteinAffectAllelesArchitectureBindingBinding ProteinsBiochemicalChromatinChromosome StructuresCodeComplexDataDevelopmentDevelopmental ProcessEnhancersEnvironmentEpigenetic ProcessFeedbackGene ClusterGene ExpressionGene FamilyGenerationsGeneticGenetic Enhancer ElementGenetic TranscriptionGenomicsGreekHumanIn SituIslandLightLinkMediatingMessenger RNAMolecularMusNeurodevelopmental DisorderNeuronal DifferentiationNuclearNuclear ProteinsOlfactory PathwaysOther GeneticsPhasePhase TransitionProcessProductionPropertyProteinsRNARNA-Binding ProteinsReceptor GeneRegulationRegulator GenesReportingRepressionRoleSignal TransductionSpecificityStructureSystemTranscriptional RegulationUntranslated RNAYeastsexperimental studygene translocationgenetic approachgenomic locusin vivoinsightinterdisciplinary approachnerve stem cellnovelolfactory receptorolfactory sensory neuronsprogramspromoterreceptor expressionrecruittranscription factor
项目摘要
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
> 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。
神秘的基因调节过程。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,仍不清楚的是OR等位基因是通过什么过程被激活的。
招募到希腊岛枢纽和机制,确保只有一个OR等位基因将保持稳定
与包含许多增强子元件的多染色体结构相关。我们的初步
数据表明,发育中短暂的OR转录和新生OR mRNA的产生有助于
到希腊岛枢纽的OR等位基因的招募和OR基因的选择。因此,我们建议遗传
这些实验将确定正义OR mRNA的哪些序列是必需的,并且足以
招募反式OR增强子,哪些蛋白质识别新生OR mRNA,
这些蛋白质必须组装多增强子/OR复合物。这些实验不仅会
光或基因选择的神秘过程,但也将提供一般的分子原理,
在细胞分化过程中介导基因组区室化的机制。
项目成果
期刊论文数量(0)
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Stavros Lomvardas其他文献
Stavros Lomvardas的其他文献
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{{ truncateString('Stavros Lomvardas', 18)}}的其他基金
The "olfactosome" as a biomolecular condensate
作为生物分子凝聚物的“嗅觉体”
- 批准号:
10669291 - 财政年份:2022
- 资助金额:
$ 48.05万 - 项目类别:
Principles of zonal olfactory receptor gene expression
带状嗅觉受体基因表达原理
- 批准号:
10350605 - 财政年份:2020
- 资助金额:
$ 48.05万 - 项目类别:
Interrogating genome folding trajectories in health and disease
探究健康和疾病中的基因组折叠轨迹
- 批准号:
10473744 - 财政年份:2020
- 资助金额:
$ 48.05万 - 项目类别:
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:
10614532 - 财政年份:2020
- 资助金额:
$ 48.05万 - 项目类别:
Principles of zonal olfactory receptor gene expression
带状嗅觉受体基因表达原理
- 批准号:
10570848 - 财政年份:2020
- 资助金额:
$ 48.05万 - 项目类别:
Interrogating genome folding trajectories in health and disease
探究健康和疾病中的基因组折叠轨迹
- 批准号:
10685554 - 财政年份:2020
- 资助金额:
$ 48.05万 - 项目类别:
Deciphering mechanisms of COVID-19 induced anosmia
解读 COVID-19 引起的嗅觉丧失的机制
- 批准号:
10176800 - 财政年份:2020
- 资助金额:
$ 48.05万 - 项目类别:
Non-cell autonomous disruption of genomic interactions as a cause of dementia
基因组相互作用的非细胞自主破坏是痴呆的原因
- 批准号:
10712217 - 财政年份:2020
- 资助金额:
$ 48.05万 - 项目类别:
Interrogating genome folding trajectories in health and disease
探究健康和疾病中的基因组折叠轨迹
- 批准号:
10266185 - 财政年份:2020
- 资助金额:
$ 48.05万 - 项目类别:
Interrogating genome folding trajectories in health and disease
探究健康和疾病中的基因组折叠轨迹
- 批准号:
10117398 - 财政年份:2020
- 资助金额:
$ 48.05万 - 项目类别: