Information Integration and Energy Expenditure in Eukaryotic Gene Regulation

真核基因调控中的信息整合和能量消耗

• 批准号: 9899260
• 负责人: Angela H DePace
• 金额: $ 44.58万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-10 至 2021-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899260
• 关键词: Affinity; Animal Model; Area; Bacteria; Binding; Binding Sites; Biological Models; Biology; CREBBP gene; Chromatin; Complex; DNA; DNA Methylation; DNA Sequence; DNA-Directed RNA Polymerase; Data; Dependence; Developmental Gene; Disease; Drosophila genus; Drosophila melanogaster; Embryo; Energy Metabolism; Energy-Generating Resources; Enhancers; Equilibrium; Eukaryota; Evolution; Foundations; Gene Expression Regulation; Genes; Genetic Transcription; Genome; Graph; Laboratories; Lead; Light; Measures; Mediating; Mediator of activation protein; Medicine; Methods; Modeling; Molecular; Mutagenesis; Nucleosomes; Pattern; Phenotype; Physics; Plant Roots; Play; Positioning Attribute; Post-Translational Protein Processing; Process; Property; Proteins; Recording of previous events; Regulation; Role; Study models; System; Testing; Theoretical Studies; Thermodynamics; Time; Transcriptional Regulation; Work; base; chromatin modification; chromatin remodeling; design; experimental study; flexibility; histone modification; information processing; interdisciplinary collaboration; knock-down; mRNA Expression; mathematical methods; mathematical model; mathematical theory; neglect; protein expression; recruit; response; transcription factor

PROJECT ABSTRACT Gene regulation – how genes are turned on in the right place, at the right time and in the right amount – is a problem central to most areas of biology and medicine. Our understanding of gene regulation began with classical studies in bacteria, which introduced the idea that proteins called “transcription factors” (TFs) determine which gene is turned on by binding to regulatory DNA sequences and recruiting RNA polymerase (RNAP). The situation in eukaryotes, however, is far more complicated. We focus in this proposal on two critical aspects of eukaryotic gene regulation that are not addressed in the bacterial paradigm. First, eukaryotic DNA is packaged into chromatin and accessibility to TF binding sites is dynamically re-organised by continuously expending external sources of energy, such as ATP. Second, in eukaryotes multi-protein co- regulators such as mediator and CREB-binding protein (CBP) intercede between TFs and RNAP, serving as “integrators” of regulatory information. Pioneering studies from several laboratories have identified many of the molecular components involved in this regulatory complexity, however, the quantitative concepts used to reason about how eukaryotic gene regulation are still largely based on the bacterial paradigm. This is an alarming discrepancy in light of the central importance of gene regulation. In recent work, we used mathematical models rooted in physics to show that this bacterial paradigm cannot account for experimentally measured data in eukaryotes. We examined, in particular, the question of how sharply a gene is turned on in response to a TF, an important property in many contexts. We introduced new concepts for analyzing information integration by co-regulators and energy expenditure and showed how these processes could explain the observed sharpness. In this proposal, we seek to build upon this highly-productive, inter-disciplinary collaboration. We will integrate mathematical theory with quantitative experiments in the well-studied model organism Drosophila melanogaster to identify which molecular mechanisms of information integration and energy expenditure are involved in regulating the developmental gene hunchback, whose sharp expression is crucial for patterning the early fruitfly embryo. As in the classical bacterial studies, we anticipate that a deep analysis of this particular gene will provide a new foundation on which to understand in quantitative terms the regulation of other eukaryotic genes and thus, that this study will have broad impact across biology and medicine.

项目摘要 基因调控——基因如何在正确的地点、正确的时间和正确的时间被开启 数量——是我们对生物学和医学大多数领域的理解的核心问题。 基因调控始于细菌的经典研究，该研究引入了蛋白质 称为“转录因子”(TF) 的基因通过与调控因子结合来决定被开启 然而，DNA 序列和募集 RNA 聚合酶 (RNAP) 的情况。 情况要复杂得多。我们在这个提案中重点关注真核基因的两个关键方面。 细菌范式中未涉及的调控首先，包装真核DNA。 进入染色质，并且 TF 结合位点的可及性通过不断地动态重组 消耗外部能量来源，例如 ATP。 其次，在真核生物中，多蛋白质共同作用。 诸如介质和 CREB ​​结合蛋白 (CBP) 等调节因子在 TF 和 RNAP，作为多项监管信息的开创性研究的“整合者”。 实验室已经鉴定出许多参与这一监管的分子成分 然而，复杂性是用于推理真核基因如何运作的定量概念 监管仍然主要基于细菌范式，这是一个令人震惊的差异。 鉴于基因调控的核心重要性，我们使用了数学模型。 植根于物理学，表明这种细菌范式无法通过实验来解释 我们特别研究了真核生物中的测量数据。 打开以响应 TF，这是在许多情况下的重要属性，我们引入了新的属性。 用于分析共同监管者的信息整合和能源支出的概念 展示了这些过程如何解释观察到的清晰度。在这个提案中，我们寻求。 在这种高效的跨学科合作的基础上，我们将进行整合。 在经过充分研究的模型生物体中进行定量实验的数学理论 果蝇识别信息整合和信息整合的分子机制 能量消耗参与调节驼背的发育基因，其尖锐 与经典细菌研究一样，表达对于早期果蝇胚胎的形成至关重要。 我们预计对这个特定基因的深入分析将为 以定量的方式理解其他真核基因的调节，从而， 研究将对生物学和医学产生广泛影响。