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.

项目摘要动物的发展对于多种扰动非常强大。动物能够尽管人口遗传差异很大，但成功发展为健康的成年人以及在发育过程中胚胎暴露的环境和内在波动。但是，发展并不是无限鲁棒的，甚至很小的变化，例如发育中的SNP 增强剂，可能导致发育缺陷。我的长期研究目标是阐明如何对编码开发程序的调节DNA的一些变化被容忍，而其他人则具有戏剧性的表型效应。该建议描述了确定阴影增强剂提供的机制的工作发展系统承受扰动的能力。阴影增强器是看似多余的增强子，可以控制单个基因并驱动相同时空表达模式。由阴影增强子组控制的发展基因可以更好地承受扰动比单个增强子控制的基因。阴影增强剂是一个普遍的功能发育，已在昆虫，哺乳动物和植物中发现。〜1000的调查果蝇中的发育基因发现，被检查的基因座中有近三分之二包含一组阴影增强剂。尽管它们的重要性，但没有可靠的机制增强子缓冲驱动器驱动稳健的基因表达模式。解剖这些机制鲁棒性将使我们能够预测哪些类型的扰动开发系统可以成功缓冲和哪种类型是无法忍受的，并合理化为什么开发某些步骤可能比其他人更脆弱。为了确定阴影增强子鲁棒性的机制，该提议描述了定量实验测量和阴影数学建模的组合在正常条件和扰动下增强子功能。这项工作的结果将区分在两个假设之间解释了阴影增强子如何驱动基因表达的强大模式面对两种不可避免的噪声，这是由离散的分子过程和外部产生的对系统的扰动。这些项目的成功也将洞悉特定功能阴影增强剂的特定类型和扰动幅度可能会调节发展过程。鉴于阴影增强子在控制发展中的流行率神经rest规格和胸腺细胞发育等过程，了解其机制行动可能会洞悉为什么某些发展系统比其他制度更脆弱，而可以指导为发现非编码DNA发育缺陷的致病突变的努力。