Genomic Regulation at the Nuclear Periphery

核外围的基因组调控

• 批准号: 8443983
• 负责人: MEGAN C KING
• 金额: $ 24.94万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8443983
• 关键词: Address; Affect; Animal Model; Architecture; Automobile Driving; Binding Sites; Biological Models; Cell Nucleus; Cells; Chromatin; Chromosome Structures; Chromosomes; Code; Complex; Conflict (Psychology); Confusion; Data; Data Set; Disease; Elements; Emery-Dreifuss Muscular Dystrophy; Engineering; Fission Yeast; Gene Expression Profile; Gene Expression Regulation; Gene Order; Genes; Genetic Transcription; Genome; Genomics; Goals; Hereditary Disease; Human; Individual; Link; Location; Mammalian Cell; Maps; Membrane Proteins; Modeling; Mutate; Mutation; Nuclear; Nuclear Envelope; Nuclear Inner Membrane; Organism; Output; Pathway interactions; Peripheral; Process; Property; Proteins; Regulation; Regulatory Pathway; Reporter; Reporter Genes; Role; Saccharomyces cerevisiae; Scientist; Site; Stimulus; Synteny; System; Testing; Tissues; Transcriptional Regulation; Work; Yeast Model System; Yeasts; base; cell type; comparative genomics; emerin; gene repression; genome sequencing; genome-wide; human disease; insight; preference; public health relevance; response; treatment strategy

DESCRIPTION (provided by applicant): For over one hundred years, scientists have observed spatial preferences for the organization of the chromosomes within the nucleus. While we have now deciphered the entire genome sequences of eukaryotic species from yeasts to humans, how those genomes are physically organized to support genomic functions remains an open question. Within the last few years, several studies in yeast and mammalian models have suggested that association of genes with the nuclear periphery, likely with inner nuclear membrane proteins, acts to regulate transcription. The importance of these studies is underscored by the discovery that several human diseases are associated with mutations within integral inner nuclear membrane proteins including emerin, which causes Emery-Dreifuss Muscular Dystrophy (EDMD). Treatment strategies are extremely challenging to devise, however, since there remains substantial confusion over two key issues of how the nuclear periphery influences transcription: 1) in yeast, association with the nuclear periphery appears to activate some genes while repressing others, and 2) it remains controversial whether heterologously driving a reporter gene to the periphery is sufficient to induce transcriptional repression in mammalian cells. In this proposal, our strategy is to derive genome-wide maps of chromatin-inner nuclear membrane interactions in two yeast models, S. cerevisiae and S. pombe (Aim 1). These organisms display correspondence of 80% of their protein coding genes while lacking significant synteny; we can leverage these properties to identify genes (and the regulatory pathways they contribute to) with conserved sites for inner nuclear membrane association, which we predict will reflect functional importance. In Aim 2, we will examine how regulatory stimuli alter the association of genes with the nuclear periphery, assess the requirement for specific inner nuclear membrane proteins in the regulation of these genes, and test the ability of engineered and reversible tethers to recapitulate gene regulation at the nuclear periphery. Our long-term goal is to understand how we might ameliorate the changes in the transcriptome that result from mutations in inner nuclear membrane proteins, and establish paradigms to allow us to devise strategies to tackle a growing number of genetic diseases including EDMD, which are collectively called "nuclear envelopathies".

描述（由申请人提供）： 一百多年来，科学家观察到了对核内染色体组织的空间偏好。虽然我们现在已经将真核物种的整个基因组序列从酵母到人解密，但这些基因组是如何进行物理组织以支持基因组功能仍然是一个悬而未决的问题。在过去的几年中，对酵母和哺乳动物模型的一些研究表明，基因与内部核膜蛋白可能与核周围的关联起来可以调节转录。这些研究的重要性强调了一些发现，即几种人类疾病与包括Emerin在内的整体内部核膜蛋白中的突变有关，这些突变导致emery-dreifuss肌肉营养不良（EDMD）。但是，设计策略的设计极具挑战性，因为核周围如何影响转录的两个关键问题仍然存在很大的困惑：1）在酵母中，与核周围的关联似乎会激活某些基因，同时抑制其他基因，而2）它仍然存在争议，是否仍然有争议地促进了一个记者基因对外围的症状良好的症状症状，这是否足以促进肌肉。在此提案中，我们的策略是在两个酵母模型（酿酒酵母和pombe S. pombe）中得出染色质核膜相互作用的全基因组图（AIM 1）。这些生物在缺乏显着同步的同时，表现出80％的蛋白质编码基因的对应关系。我们可以利用这些特性来识别内部核膜关联的保守位点的基因（以及它们贡献的调节途径），我们预测这将反映功能重要性。在AIM 2中，我们将研究调节性刺激如何改变基因与核周围的缔合，评估对这些基因调节中特定内部核膜蛋白的需求，并测试工程和可逆的Tethers在核外围概括基因调控基因的能力。我们的长期目标是了解我们如何改善因内核膜蛋白突变而导致的转录组变化，并建立范式，以使我们能够制定策略来解决越来越多的遗传疾病，包括EDMD，这些遗传疾病统称为“核壳”。