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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）：