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方，在正确的时间和正确的时间打开 数量-是生物学和医学大多数领域的核心问题。我们理解 基因调控始于对细菌的经典研究，它引入了蛋白质 一种称为“转录因子”（TF）的蛋白质通过与调控因子结合来决定哪个基因被打开。 DNA序列和募集RNA聚合酶（RNAP）。然而，真核生物的情况是， 要复杂得多我们的建议集中在真核基因的两个关键方面， 在细菌范例中没有涉及的调节。首先，真核DNA被包装 进入染色质和TF结合位点的可及性是动态重组的， 消耗外部能源，如ATP。第二，在真核生物中，多蛋白质共- 调节剂如介体和CREB结合蛋白（CBP）在TF和 RNAP，作为监管信息的“整合者”。几项开创性的研究 实验室已经鉴定了许多参与这种调节的分子组分， 复杂性，然而，用于推理真核基因如何表达的定量概念 调节仍然主要基于细菌范例。这是一个令人震惊的差异， 鉴于基因调控的核心重要性。在最近的工作中，我们使用数学模型 植根于物理学，以表明这种细菌范例不能解释实验 真核生物的测量数据。我们特别研究了一个基因 在许多情况下，这是一个重要的属性。我们介绍了新的 用于分析协同调节器和能量消耗的信息集成的概念， 显示了这些过程如何解释观察到的锐度。在这一建议中，我们寻求 建立在这种高效的跨学科合作之上。我们将整合 数学理论与定量实验在充分研究的模式生物 果蝇，以确定哪些分子机制的信息整合和 能量消耗参与调节发育基因hunchback， 表达对于形成早期果蝇胚胎的图案至关重要。在经典的细菌研究中， 我们预计，对这一特定基因的深入分析将提供一个新的基础， 以定量的方式了解其他真核基因的调控，因此， 这项研究将对生物学和医学产生广泛的影响。