Genomic Regulation at the Nuclear Periphery

核外围的基因组调控

基本信息

批准号：
8610936
负责人：
MEGAN C KING
金额：
$ 20.81万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8610936
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

项目摘要

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，科学家们观察了细胞核内染色体组织的空间偏好。虽然我们现在已经破译了从酵母到人类的真核物种的整个基因组序列，但这些基因组如何物理组织以支持基因组功能仍然是一个悬而未决的问题。在过去的几年里，对酵母和哺乳动物模型的几项研究表明，基因与核外围的关联（可能与内核膜蛋白的关联）起到调节转录的作用。这些研究的重要性是因为我们发现一些人类疾病与完整的内核膜蛋白（包括导致埃默里-德莱福斯肌营养不良症（EDMD）的艾莫蛋白）的突变有关。然而，设计治疗策略极具挑战性，因为对于核外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，与核外围的关联似乎激活了一些基因，同时抑制了其他基因，2）它异源驱动报告基因至外周是否足以诱导哺乳动物细胞的转录抑制仍存在争议。在本提案中，我们的策略是在两种酵母模型（酿酒酵母和粟酒裂殖酵母）中获得染色质与核膜相互作用的全基因组图谱（目标 1）。这些生物体显示出 80% 的蛋白质编码基因的对应性，但缺乏显着的同线性；我们可以利用这些特性来识别具有内核膜关联保守位点的基因（以及它们所贡献的调控途径），我们预测这将反映功能重要性。在目标 2 中，我们将研究调节刺激如何改变基因与核外围的关联，评估调节这些基因对特定内核膜蛋白的需求，并测试工程化和可逆系绳重述基因调节的能力。核外围。我们的长期目标是了解如何改善由内核膜蛋白突变引起的转录组变化，并建立范式，使我们能够制定策略来应对越来越多的遗传疾病，包括 EDMD，这些疾病统称为 EDMD。称为“核包膜病”。