HIGH RESOLUTION EPIGENOMIC MAPS OF YEAST IN RESPONSE TO ENVIRONMENTAL STRESS

酵母响应环境压力的高分辨率表观基因组图

基本信息

批准号：
10675035
负责人：
B FRANKLIN PUGH
金额：
$ 67.22万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10675035
关键词：
Acute Architecture Binding Biological Assay Budgets Cell model Cells Chromatin Chronic stress Collection Complex DNA DNA Polymerase II Data Data Set Development Diagnostic Disease Enhancers Event Funding Gene Activation Gene Expression Regulation Genes Genetic Transcription Genome Genomics Goals Grant Heat-Shock Response Hour Human Life Maps Measurable Measures Mediator Molecular Nature Oxidative Stress Pathway interactions Peptide Initiation Factors Peroxides Process Proteins Publishing Regulation Regulator Genes Repression Research Project Grants Resolution Role SAGA Saccharomyces Saccharomycetales Signal Transduction Starvation Stress Structure System Testing Tissues Transcription Elongation Transcription Initiation United States National Institutes of Health Work Yeasts acute stress biological adaptation to stress cofactor computational pipelines cost epigenome epigenomics extracellular gene environment interaction gene function gene induction gene synthesis genetic manipulation genetic regulatory protein genome-wide histone modification insight novel promoter protein function response transcription factor

项目摘要

Gene regulation is central to all life, normal and diseased. The long-term goal of this research project is to un- derstand at single bp resolution the molecular organization (architecture) of proteins assembled on the Sac- charomyces (budding yeast) genome. Budding yeast represent an ideal model cellular system due to its simple genome, ease of genetic manipulation, and conservation of transcription and chromatin regulators with human cells. By understanding the precise molecular architecture of epigenomes, we gain a holistic view of genome regulation mechanisms. This project will build on our published set of genome-wide ChIP-exo data that com- prehensively measures the yeast epigenome consisting of over 400 distinct proteins. This expansion will in- volve understanding how epigenomes are reprogrammed by environmental signals. Two broad classes of re- programming will be examined: acute stress responses (e.g., heat shock and oxidative stress) and long-term unfolding of developmental pathways (e.g., starvation responses) brought on by chronic stress. Responses to acute stress reveal molecular architectures that pre-exist in the cell and then re-organize within a few minutes of sensing extracellular signaling. These events are typically transient and so must be captured upon reaching their temporal maxima. In contrast, developmental pathways unfold over hours in yeast and typically rely on de novo synthesis of gene-specific transcription factors. This project will map the precise positional organiza- tion of hundreds of epigenomic components in response to heat shock and oxidative stress, and smaller set of components in response to a much broader array of acute stresses and developmental pathways. This project will also define the functional interdependencies of epigenomic factors, with particular focus on the gene in- duction cofactors Mediator and SAGA. Relevant components of induced transcription will be rapidly depleted, then their impact on Mediator and SAGA binding to promoters examined. Other interdependencies, informed by the organization of epigenomes that will be defined during reprogramming/induction will also be examined. Together these aims will help provide a more thorough understanding of the protein architecture of gene regu- lation that should allow computational prediction of novel gene-environment interactions in diseased tissue.

基因调控对于所有生命（无论是正常生命还是患病生命）至关重要。该研究项目的长期目标是以单碱基对的分辨率了解在囊上组装的蛋白质的分子组织（结构） Charomyces（芽殖酵母）基因组。芽殖酵母因其简单而代表了理想的细胞系统模型基因组、易于遗传操作以及人类转录和染色质调节因子的保护细胞。通过了解表观基因组的精确分子结构，我们获得了基因组的整体视图监管机制。该项目将建立在我们发布的一组全基因组 ChIP-exo 数据的基础上，这些数据包括：全面测量由 400 多种不同蛋白质组成的酵母表观基因组。此次扩建将在—— 涉及了解表观基因组如何通过环境信号重新编程。两大类重新将检查编程：急性应激反应（例如热休克和氧化应激）和长期应激反应慢性压力引起的发育途径（例如饥饿反应）的展开。回应急性应激揭示了细胞中预先存在的分子结构，然后在几分钟内重新组织感测细胞外信号传导。这些事件通常是暂时的，因此必须在到达时捕获他们的时间最大值。相比之下，酵母的发育途径需要数小时才能展开，并且通常依赖于基因特异性转录因子的从头合成。该项目将绘制精确的组织定位图数百种表观基因组成分响应热休克和氧化应激，以及较小的一组应对更广泛的急性压力和发展途径的组成部分。这个项目还将定义表观基因组因素的功能相互依赖性，特别关注基因诱导辅因子Mediator 和SAGA。诱导转录的相关成分将迅速耗尽，然后检查它们对 Mediator 和 SAGA 与启动子结合的影响。其他相互依赖性，知情还将检查在重编程/诱导期间定义的表观基因组的组织。这些目标共同将有助于更全面地了解基因调控的蛋白质结构。应该允许对患病组织中新的基因-环境相互作用进行计算预测。