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: 10700136
• 负责人: Gavin Ryan Rice
• 金额: $ 12.5万
• 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/10700136
• 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; 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.

项目摘要 拟议研究的目的是了解如何修改基因调节网络（GRN） 在整个身体中反复生成结构。 GRN组织了数百个基因的激活 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。人们认为，在身体不同组织中GRN的重复使用会产生重复的身体 诸如头发，肌肉或神经元之类的部分。通常认为这是通过重新部署 在GRN中高度位于新环境中的因素。尽管努力确定导致的突变 GRN重新部署，它仍然难以捉摸。拟议的研究将确定导致的遗传变化 重新部署了在果蝇中广泛表征和操纵的GRN。 此外，我将调查如何在组织特异性中修改GRN的结构 时尚。大多数研究仅关注控制GRN的上游因素，但我将使用基因组。 研究网络中下游基因的技术是如何通过其激活并连接到其的技术 上游转录因子。我将确定相同的调节元素和直接绑定位点是 在所有组织中或在组织之间有所不同。该建议将使用尖端转基因技术 不仅通过遗传操纵来描述关联，而且可以测试预测。我将确定哪个 遗传变化是必需的，足以进行GRN的重新部署和修饰。最终 目标是编辑基因组，以将GRN重新部署为幼稚的背景。 拟议的工作将产生一个最完整的模型之一。 组织。该模型可以帮助我们了解哪些遗传变化可能会将GRN转移到新的组织中，并且 在新环境中，整个GRN是否会重新部署。人类健康状况很大 诸如先天缺陷之类的影响已追溯到上游因素的调节元素中的突变 这导致了新位置的生态表达和重复结构的产生。提议 工作将建立一个通用模型，以实现生态表达的原因，从而提供一般见解 grns的架构管理各种系统中的重复结构。