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.

抽象的 赖氨酸脱甲基酶 5 (KDM5) 转录调节因子家族对于正常细胞的正常表达非常重要 发育及其失调与智力障碍和多种形式的智力障碍有关 癌症。然而，由于缺乏对 KDM5 蛋白正常生理作用的了解， 阻碍了我们对它们的损失或增益如何导致疾病状态的理解。因此，长期目标 这些研究的目的是确定 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进行调控程序。具体来说，我们重点 定义 KDM5 独立于其良好的转录调控机制 确定组蛋白去甲基化酶活性。阐明不依赖去甲基化酶的重要性 我们观察到 KDM5 执行其基本功能，这凸显了基因调控机制 发育活动与其酶活性分开。然而，分子机制 KDM5 的这些非规范功能的背后仍然未知。我们的新数据显示，一个地区 KDM5 的 C 末端内不具有先前已知的功能，这是生存所必需的。 此外，相互作用组研究将 KDM5 的 C 末端与非特异性致死 (NSL) 联系起来 转录激活复合物。这些和其他数据引导我们提出中心假设 KDM5 与 NSL 复合物相互作用来协调基因表达程序 动物的生存。为了测试这一点，我们将使用一系列遗传、分子和细胞生物学方法 定义对发育至关重要的 KDM5 调控的靶基因和途径，并 确定 KDM5、NSL 和转录调控之间的分子联系。这项研究是 创新之处在于我们专注于定义 KDM5 的去甲基化酶独立活性以及我们使用状态- 最先进的技术。这项工作意义重大，因为我们将提供有关 KDM5 的基本见解 与我们理解多域基因调控广泛相关的功能 蛋白质。我们的工作还有望强调 KDM5 失调的潜在机制 可能导致智力障碍和/或癌症。