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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：
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
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/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

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.

项目总结