Deconstructing and recapitulating the genetic basis of gene regulatory network redeployment

项目摘要 这项研究的目的是了解基因调控网络（GRNs）是如何被修改的。 以产生在整个身体中重复的结构。GRNs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GRNs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 部分，如头发，肌肉或神经元。一般假设，这是通过重新部署 在GRN中处于高位的因素到一个新的背景。尽管我们做了很多努力来识别导致 GRN重新部署，它仍然难以捉摸。这项拟议中的研究将确定导致 重新部署在果蝇中被广泛描述和操纵的GRN。 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GRNs的上游因素，但我将使用基因组 技术来研究网络中的下游基因是如何被激活并连接到它们的 上游转录因子我将确定是否相同的调控元件和直接结合位点， 可在所有组织中重复使用，或者在不同组织之间重复使用。这项提案将使用最先进的转基因技术 不仅能描述关联，还能通过基因操作测试预测。我会决定 遗传变化对于GRN的重新部署和修改是必要且充分的。最终 我们的目标是编辑基因组，将GRN重新部署到一个幼稚的背景中。 拟议的工作将产生一个最完整的模型，一个GRN的重新部署跨越 组织中这个模型可以帮助我们理解什么样的遗传变化可以将GRN移动到新的组织中， 是否会在新的情况下重新部署整个全球网络。具有大表型的人类健康状况 诸如出生缺陷的影响可以追溯到上游因子调节元件的突变 这导致异位表达和在新位置产生重复结构。拟议 工作将建立一个异位表达的原因的一般模型，提供一般的见解， 在各种系统中管理重复结构的GRNs架构。

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.