Non-canonical mechanisms of gene regulation by the histone demethylase KDM5

组蛋白去甲基化酶 KDM5 基因调控的非典型机制

• 批准号: 10746913
• 负责人: Julie Secombe
• 金额: $ 33.6万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10746913
• 关键词: Acetylation; Affect; Alleles; Amino Acids; Animals; Autophagocytosis; Binding; Biological; Biology; Cell physiology; Cells; Chromatin; Clinical Pathology; Complex; Data; Deletion Mutation; Development; Disease; Drosophila genus; Elements; Essential Genes; Family; Gene Expression; Gene Expression Regulation; Gene Family; Genes; Genetic; Genetic Transcription; Genomics; Goals; Human; Intellectual functioning disability; Investigation; Knowledge; Label; Link; Lysine; Malignant Neoplasms; Mediating; Missense Mutation; Molecular; Nonsense Mutation; Pathway interactions; Physiological; Production; Protein Family; Proteins; RNA Polymerase II; Regulation; Regulator Genes; Reporter; Research Proposals; Role; Series; Techniques; Terminator Codon; Tertiary Protein Structure; Testing; Time; Transcriptional Activation; Transcriptional Regulation; Work; histone demethylase; in vivo; innovation; insight; male; model organism; mutant; programs; promoter; protein protein interaction; recruit; transcriptomics

Abstract The lysine demethylase 5 (KDM5) family of transcriptional regulators are important for normal development and their dysregulation is associated with intellectual disability and with several forms of cancer. However, a lack of understanding of the normal physiological roles of KDM5 proteins has hindered our understanding of how their loss or gain leads to disease states. Thus, the long-term goal of these studies is to define the molecular mechanisms by which KDM5 regulates essential gene regulatory programs using the genetically elegant model organism Drosophila. Specifically, we focus on defining mechanisms of transcriptional regulation by KDM5 that are independent of its well- established histone demethylase activity. The importance of illuminating demethylase-independent gene regulatory mechanisms is highlighted by our observation that KDM5 carries out its essential developmental activities separately from its enzymatic activity. However, the molecular mechanisms underlying these non-canonical functions of KDM5 remain unknown. Our new data show that a region within the C-terminus of KDM5 that has no previously known function is required for viability. Moreover, interactome studies link the C-terminus of KDM5 to the non-specific lethal (NSL) transcriptional activation complex. These and other data lead us to propose the central hypothesis that a KDM5 interacts with the NSL complex to orchestrate gene expression programs needed for animal survival. To test this, we will use a range of genetic, molecular and cell biological approaches to define the target genes and pathways regulated by KDM5 that are critical for development, and to determine the molecular links between KDM5, NSL and transcriptional regulation. This study is innovative in our focus on defining demethylase-independent activities of KDM5 and our use of state- of-the-art techniques. This work is significant because we will provide fundamental insights into KDM5 function that will be broadly relevant for our understanding of gene regulation by multi-domain proteins. Our work is also expected to highlight potential mechanisms by which KDM5 dysregulation could contribute to intellectual disability and/or cancer.

摘要 赖氨酸脱甲基酶5(KDM5)家族的转录调控对正常 发育及其失调与智力残疾和几种形式的 癌症。然而，由于缺乏对KDM5蛋白正常生理作用的了解， 阻碍了我们对他们的得失如何导致疾病状态的理解。因此，长期目标是 这些研究的重点是确定KDM5调节必需基因的分子机制 使用基因优雅的模式生物果蝇的监管计划。具体地说，我们专注于 关于KDM5转录调控机制的定义，这些机制独立于其良好的 已确定组蛋白去甲基酶活性。阐明脱甲基酶非依赖性的重要性 我们观察到KDM5执行其必需的基因调控机制 发育活性与其酶活性分开。然而，分子机制 KDM5在这些非正则功能中的潜在作用尚不清楚。我们的新数据显示，一个地区 在KDM5的C末端，没有已知的功能是生存所必需的。 此外，交互作用组研究将KDM5的C末端与非特异性致死(NSL)联系起来 转录激活复合体。这些数据和其他数据引导我们提出了中心假说 KDM5与NSL复合体相互作用，协调所需的基因表达程序 动物的生存。为了测试这一点，我们将使用一系列的遗传、分子和细胞生物学方法。 确定KDM5调控的对发育至关重要的靶基因和通路，并 确定KDM5、NSL和转录调控之间的分子联系。这项研究是 我们在重点定义KDM5的不依赖于甲基酶的活性以及我们使用状态- 最先进的技术。这项工作意义重大，因为我们将提供对KDM5的基本见解 与我们对多结构域基因调控的理解广泛相关的功能 蛋白质。我们的工作也有望突出KDM5调节失调的潜在机制 可能导致智力残疾和/或癌症。