Deconstructing and recapitulating the genetic basis of gene regulatory network redeployment

解构和概括基因调控网络重新部署的遗传基础

• 批准号: 10506582
• 负责人: Gavin Ryan Rice
• 金额: $ 10万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-07 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10506582
• 关键词: Address; Adult; Affect; Animals; Architecture; Back; Behavior; Binding Sites; Biological Models; Body Surface; Body part; Cells; Congenital Abnormality; Data; Development; Drosophila genus; Drosophila melanogaster; Ectopic Expression; Elements; Enhancers; Event; Female; Foundations; Generations; Genes; Genetic; Genetic Engineering; Genital; Genitalia; Genome; Genomics; Goals; Hair; Health; Human; Lead; Location; Modeling; Modification; Morphology; Muscle; Mutation; Neurons; Organism; Outcome; Phenotype; Processed Genes; Recurrence; Regulation; Regulatory Element; Research; Shapes; Signaling Molecule; Specific qualifier value; Structure; System; Techniques; Testing; Tissues; Transgenic Organisms; Variant; Work; appendage; arms race; cell type; gene regulatory network; genetic manipulation; genome editing; genome-wide; insight; male; network architecture; novel; physical property; programs; transcription factor; transcription factor USF

PROJECT SUMMARY The goal of the proposed research is to understand how gene regulatory networks (GRNs) are modified to generate structures repeated throughout the body. GRNs organize the activation of hundreds of genes under the control of one or few transcription factors or signaling molecules. The activation of specific GRNs designate cell type. The reuse of a GRN in different tissues of the body is thought to generate repeated body parts such as hair, muscles, or neurons. This is generally hypothesized to proceed by the redeployment of factors situated high within the GRN to a new context. Despite much effort to identify the mutations that lead to GRN redeployment, it has remained elusive. The proposed research will identify the genetic changes that led to the redeployment of a GRN that has been extensively characterized and manipulated in Drosophila. Furthermore, I will investigate how the architecture of a GRN can be modified in a tissue-specific fashion. Most studies have focused only on the upstream factors that control GRNs, but I will use genomic techniques to investigate how downstream genes in the network are activated by and connected to their upstream transcription factors. I will determine if the same regulatory elements and direct binding sites are reused in all tissues or if they vary between tissues. This proposal will use cutting edge transgenic techniques to not only describe associations but test predictions through genetic manipulation. I will determine which genetic changes are necessary and sufficient for the redeployment and modification of a GRN. The ultimate goal will be to edit the genome to redeploy a GRN into a naive background. The proposed work will generate one of the most complete models a GRN’s redeployment across tissues. This model can help us understand what genetic changes may move a GRN into a new tissue and whether the full GRN will be redeployed in the new context. Human health conditions with large phenotypic effects such as birth defects have been traced back to mutations in regulatory elements of upstream factors which lead to ectopic expression and the generation of repeated structures in new locations. The proposed work will establish a general model for causes of ectopic expression, providing general insights into the architecture of GRNs governing repeated structures in a variety of systems.

项目总结 这项拟议的研究的目标是了解基因调控网络(GRN)是如何被修改的 以产生遍及全身的重复结构。GRN组织数百个基因的激活 在一个或几个转录因子或信号分子的控制下。特定GRN的激活 指定单元格类型。GRN在人体不同组织中的重复使用被认为可以产生重复的身体 毛发、肌肉或神经元等部位。这通常被假设为通过重新部署 位于GRN中较高位置的因素导致了新的背景。尽管花了很大力气来确定导致 在GRN重新部署后，它仍然难以捉摸。这项拟议的研究将确定导致 在果蝇中已经被广泛描述和操纵的GRN的重新部署。 此外，我将研究如何在特定组织中修改GRN的架构 时尚。大多数研究只关注控制GRN的上游因素，但我将使用基因组 研究网络中下游基因如何被其激活并连接到其上的技术 上游转录因子。我将确定相同的调控元件和直接结合位点是否 在所有组织中重复使用，或者在组织之间不同的情况下重复使用。该提案将使用尖端的转基因技术。 不仅描述关联性，而且通过基因操作来测试预测。我会决定是哪一个 基因变化是重新部署和修改GRN所必需的，也是充分的。终极的 目标是编辑基因组，将GRN重新部署到幼稚的背景中。 拟议的工作将产生GRN重新部署所涉及的最完整的模型之一 纸巾。这个模型可以帮助我们理解什么基因变化可能会将GRN转移到新的组织中，并 是否将在新的背景下重新部署完整的GRN。具有大表型的人类健康状况 出生缺陷等影响被追溯到上游因子的调节元件的突变。 这会导致异位表达，并在新的位置产生重复结构。建议数 工作将建立异位表达原因的一般模型，提供对异位表达的一般洞察 管理各种系统中重复结构的GRN的体系结构。