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Mechanisms of shadow enhancer robustness during development

开发过程中阴影增强器鲁棒性的机制

基本信息

批准号：
10478829
负责人：
Zeba B Wunderlich
金额：
$ 33.56万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-03 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10478829
关键词：
Adult Animals Anterior Automobile Driving Bioinformatics Biological Models Buffers Cells Computer Models DNA Defect Development Developmental Gene Developmental Process Disease Drosophila genus Embryo Embryonic Development Enhancers Experimental Designs Frequencies Gene Combinations Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Genetic Variation Goals Image Insecta Lead Literature Mammals Measurement Measures Messenger RNA Modeling Molecular Muscle Cells Mutation Neural Crest Neurons Noise Pattern Penetrance Performance Phase Phenotype Plants Population Prevalence Process Research Retinoscopy Surveys System Temperature Testing Thymocyte Development Time Untranslated RNA Work autism spectrum disorder causal variant cell type gene environment interaction human disease in vivo insight mathematical model mature animal novel programs promoter response spatiotemporal success transcription factor zygote

项目摘要

Project Summary Animal development is remarkably robust to many kinds of perturbations. Animals are able to successfully develop into healthy adults despite the large amount of genetic variation in the population and the environmental and intrinsic fluctuations to which the embryo is exposed during development. However, development is not infinitely robust, and even small changes, e.g. a SNP in a developmental enhancer, can lead to developmental defects. My long-term research goal is to elucidate how some changes to the regulatory DNA that encodes the developmental program are tolerated, while others have dramatic phenotypic effects. This proposal describes work to identify the mechanisms by which shadow enhancers provide developmental systems the capability to withstand perturbations. Shadow enhancers are sets of seemingly redundant enhancers that control a single gene and drive the same spatio-temporal expression pattern. Developmental genes controlled by sets of shadow enhancers can better withstand perturbations than genes controlled by a single enhancer. Shadow enhancers are a pervasive feature of development and have been found in insects, mammals, and plants. A survey of ~1000 developmental genes in Drosophila found that nearly two-thirds of examined loci contained a set of shadow enhancers. Despite their importance, there is no proven mechanism for how shadow enhancers buffer perturbations to drive robust gene expression patterns. Dissecting these mechanisms of robustness will allow us to predict what types of perturbations developmental systems can successfully buffer and what types are intolerable, and to rationalize why certain steps in development may be more fragile than others. To identify the mechanisms of shadow enhancer robustness, this proposal describes a combination of quantitative experimental measurements and mathematical modeling of shadow enhancer function under normal conditions and perturbation. The results of this work will distinguish between two hypotheses that explain how shadow enhancers drive robust patterns of gene expression in the face of both the inevitable noise that arises from discrete molecular processes and external perturbations to the system. Success in these projects will also yield insight into how specific features of shadow enhancers may be tuned to buffer specific types and amplitudes of perturbations during the developmental process. Given the prevalence of shadow enhancers in controlling developmental processes like neural crest specification and thymocyte development, understanding their mechanisms of action may give insights in to why some developmental systems are more fragile than others and may guide efforts to find causative mutations for developmental defects in non-coding DNA.

项目摘要动物的发育对各种干扰都有很强的抵抗力。动物能够尽管种群中存在大量的遗传变异，以及胚胎在发育过程中所暴露的环境和内在波动。然而，发育并不是无限稳健的，即使是微小的变化，例如，发育中的SNP，增强剂，可导致发育缺陷。我的长期研究目标是阐明编码发育程序的调节DNA的一些变化是可以容忍的，而另一些则具有显著的表型效应。该提案描述了识别阴影增强剂提供的机制的工作。发展系统的能力，以抵御扰动。阴影增强器是一套看似多余的增强子，控制着单个基因，表达模式由阴影增强器控制的发育基因可以更好地抵御受单个增强子控制的基因。阴影增强器是一个普遍的功能在昆虫、哺乳动物和植物中发现。调查约1000人果蝇发育基因的研究发现，近三分之二的检测位点包含一组阴影增强剂尽管它们很重要，但还没有证实的机制可以解释阴影增强子缓冲扰动以驱动稳健的基因表达模式。剖析这些机制鲁棒性将使我们能够预测什么类型的扰动发展系统可以成功地缓冲和什么类型是不能容忍的，并合理化为什么某些步骤的发展可能比其他人更脆弱。为了识别阴影增强器鲁棒性的机制，该提议描述了一个阴影的定量实验测量和数学建模的组合增强子函数在正常条件下和扰动。这项工作的结果将区分这两种假说解释了阴影增强子如何驱动基因表达的强大模式，面对来自离散分子过程和外部环境的不可避免的噪音，对系统的扰动。这些项目的成功还将使我们深入了解特定功能如何可以调整阴影增强器的数量以缓冲特定类型和幅度的扰动，发展过程鉴于阴影增强剂在控制发育方面的普遍性，神经嵴特化和胸腺细胞发育等过程，了解其机制行动可能会让我们深入了解为什么一些发展系统比其他系统更脆弱，可能指导寻找非编码DNA发育缺陷的致病突变的努力。