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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要拟议研究的目标是了解基因调控网络（GRN）是如何被修改的生成在全身重复的结构，GRN 组织数百个基因的激活。在一种或几种转录因子或信号分子的控制下，特定GRN的激活。指定细胞类型在身体的不同组织中重复使用 GRN 被认为会产生重复的身体。这通常是通过重新部署来进行的。尽管我们付出了很多努力来确定导致 GRN 内的突变的因素。 GRN 的重新部署仍然难以捉摸。拟议的研究将确定导致基因变化的因素。重新部署已在果蝇中广泛表征和操纵的 GRN。此外，我将研究如何在组织特异性中修改 GRN 的架构大多数研究只关注控制 GRN 的上游因素，但我将使用基因组。研究网络中的下游基因如何被其激活并与其连接的技术我将确定是否有相同的调控元件和直接结合位点。在所有组织中重复使用，或者如果它们在组织之间有所不同，该提案将使用尖端的转基因技术。我不仅要描述关联，还要通过基因操作来测试预测。基因改变对于GRN的重新部署和修改是必要且充分的。目标是编辑基因组，将 GRN 重新部署到初始背景中。拟议的工作将生成 GRN 重新部署的最完整模型之一这个模型可以帮助我们了解哪些基因变化可以将 GRN 转移到新的组织中。完整的 GRN 是否会在具有大表型的人类健康状况下重新部署。出生缺陷等影响可追溯到上游因素调控元件的突变这导致异位表达并在新位置产生重复结构。这项工作将为异位表达的原因建立一个通用模型，提供对异位表达的一般见解 GRN 的架构管理各种系统中的重复结构。