Physiological Model of Gene Regulation in Drosophila

果蝇基因调控的生理模型

基本信息

  • 批准号:
    9049559
  • 负责人:
  • 金额:
    $ 62.78万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-01-01 至 2019-01-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The goal of this proposal is to discover and interpret the code by which cis-regulatory DNA controls gene expression. Although cis-regulatory logic is reasonably well understood in bacteria and yeast, this is not the case in multicellular organisms. With a very large number of types of differentiated cells, each of which have the same genetic material but express different sets of genes, metazoans such as humans devote large regions of DNA to biologically essential regulatory functions. These regulatory regions are targets of selection and evolutionary change, and noncoding polymorphisms are connected to disease susceptibility. We have developed a new approach to understanding cis-regulatory logic based on understanding the principles that govern which configurations of bound transcription factors activate transcription and which configurations repress it. This approach is implemented in a model trained on quantitative expression data at cellular resolution from blastoderm stage embryos of Drosophila melanogaster, which we use as a naturally grown "gene chip". The model is able to correctly predict expression from DNA not used in the training procedure, including highly diverged sequence from distantly related species. We will interpret the cis-regulatory code by making use of a suite of tools applied to D. melanogaster and its sibling species D. erecta and D. virilis. The consideration of regulatory circuits across species at the resolution proposed represents a profound extension of network analysis. Supporting techniques include targeted chromosomal transformation of Drosophilid embryos, a sequence-based model of transcriptional control having an established predictive capability for a range of problems, whole-locus transgenes engineered at single-nucleotide resolution with recombineering, and methods for designing and testing synthetic enhancers. The forgoing methods will allow us to test proposed principles of cis-regulatory logic as they are developed in the context of naturally occurring and artificial sequences, and in perturbed trans-environments. Our ultimate goal is to predict the expression patterns of whole genes and synthetic enhancers directly from genomic sequence and data on transcription factor expression. These objectives are summarized the following four specific aims. 1) Design, synthesize, and experimentally test completely defined artificial enhancers that express naturally occurring or arbitrarily chosen patterns on the anterior-posterior axis. 2) Construct and experimentally test a model of the embryonic expression of the complete even-skipped locus. 3) Build a quantitative map of maternal gradients and gap gene expression in Drosophila virilis and Drosophila erecta. 4) Construct testable models of the maternal-gap-eve networks in Drosophila virilis and Drosophila erecta.
描述(由申请人提供):本提案的目标是发现和解释顺式调控DNA控制基因表达的密码。尽管顺式调控逻辑在细菌和酵母中得到了很好的理解,但在多细胞生物体中却并非如此。后生动物有大量的分化细胞,每种细胞都有相同的遗传物质,但表达不同的一组基因,像人类这样的后生动物将大片DNA用于生物学上基本的调节功能。这些调控区域是选择和进化变化的目标,非编码多态与疾病易感性有关。我们已经开发了一种新的方法来理解顺式调控逻辑,这是基于理解控制结合的转录因子的哪些配置激活转录以及哪些配置抑制转录的原则。这种方法是在一个模型中实现的,该模型以细胞分辨率的定量表达数据为基础,来自果蝇胚胎期的胚胎,我们将其用作自然生长的“基因芯片”。该模型能够正确预测训练过程中没有使用的DNA的表达,包括来自远亲物种的高度分化的序列。我们将通过使用一套适用于黑腹隐翅虫及其近亲物种直立隐翅虫和维氏隐翅虫的工具来解释顺式调控密码。在所提出的决议中考虑跨物种的调节电路代表了网络分析的深刻扩展。支持技术包括果蝇胚胎的定向染色体转化,对一系列问题具有既定预测能力的基于序列的转录控制模型,以单核苷酸分辨率和重组工程设计的全基因座转基因,以及设计和测试合成增强剂的方法。上述方法将允许我们测试所提出的顺式调节逻辑原理,因为它们是在自然发生和人工序列的背景下以及在扰动的跨环境中开发的。我们的最终目标是直接从基因组序列和转录因子表达数据预测整个基因和合成增强子的表达模式。这些目标概括为以下四个具体目标。1)设计、合成和实验测试完全定义的人工增强剂,这些人工增强剂在前后轴上表达自然发生的或任意选择的图案。2)构建了完整偶跳基因的胚胎表达模型并进行了实验验证。3)构建了果蝇和直立果蝇的母体梯度和GAP基因表达的定量图谱。4)构建了果蝇和直立果蝇母体-缝隙-夏娃网络的可测模型。

项目成果

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John B. Reinitz其他文献

John B. Reinitz的其他文献

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{{ truncateString('John B. Reinitz', 18)}}的其他基金

Physiological Model of Gene Regulation in Drosophila
果蝇基因调控的生理模型
  • 批准号:
    8062150
  • 财政年份:
    2011
  • 资助金额:
    $ 62.78万
  • 项目类别:
Physiological Model of Gene Regulation in Drosophila
果蝇基因调控的生理模型
  • 批准号:
    10205184
  • 财政年份:
    2011
  • 资助金额:
    $ 62.78万
  • 项目类别:
Physiological Model of Gene Regulation in Drosophila
果蝇基因调控的生理模型
  • 批准号:
    10415987
  • 财政年份:
    2011
  • 资助金额:
    $ 62.78万
  • 项目类别:
Physiological Model of Gene Regulation in Drosophila
果蝇基因调控的生理模型
  • 批准号:
    8448771
  • 财政年份:
    2011
  • 资助金额:
    $ 62.78万
  • 项目类别:
Physiological Model of Gene Regulation in Drosophila
果蝇基因调控的生理模型
  • 批准号:
    8862689
  • 财政年份:
    2011
  • 资助金额:
    $ 62.78万
  • 项目类别:
Physiological Model of Gene Regulation in Drosophila
果蝇基因调控的生理模型
  • 批准号:
    9203640
  • 财政年份:
    2011
  • 资助金额:
    $ 62.78万
  • 项目类别:
Physiological Model of Gene Regulation in Drosophila
果蝇基因调控的生理模型
  • 批准号:
    10633284
  • 财政年份:
    2011
  • 资助金额:
    $ 62.78万
  • 项目类别:
Physiological Model of Gene Regulation in Drosophila
果蝇基因调控的生理模型
  • 批准号:
    8228040
  • 财政年份:
    2011
  • 资助金额:
    $ 62.78万
  • 项目类别:
Shared Equipment Grant for Purchase of a Leica TCS SP5 Confocal Microscope
用于购买 Leica TCS SP5 共焦显微镜的共享设备补助金
  • 批准号:
    7793767
  • 财政年份:
    2010
  • 资助金额:
    $ 62.78万
  • 项目类别:
Physiological Model of Gene Regulation in Drosophila
果蝇基因调控的生理模型
  • 批准号:
    7929841
  • 财政年份:
    2009
  • 资助金额:
    $ 62.78万
  • 项目类别:

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