Functions and Regulation of Centromeric Transcription

着丝粒转录的功能和调控

• 批准号: 10604267
• 负责人: Hong Liu
• 金额: $ 30.4万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604267
• 关键词: Affect; Aneuploidy; Antineoplastic Agents; Cell Cycle; Cell Cycle Stage; Centromere; Chromatin; Chromosomal Instability; Chromosomal Stability; Chromosome Segregation; Clinical; Cyclin-Dependent Kinases; DNA Sequence; Data; Defect; Deposition; Development; Disease; Epigenetic Process; Eukaryota; Future; Gene Expression; Genetic Transcription; Goals; Histones; Human; Knowledge; Maintenance; Malignant Neoplasms; Mission; Mitosis; Mitotic; Outcome; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Process; Production; Proteins; Public Health; Publishing; RNA; RNA Polymerase II; Regulation; Research; Role; Satellite DNA; Testing; Therapeutic Agents; Translations; United States National Institutes of Health; Untranslated RNA; Variant; Yeasts; base; cancer therapy; cohesion; drug discovery; epigenetic regulation; histone modification; innovation; knock-down; novel; novel strategies; novel therapeutic intervention; therapeutic target; tool; tumorigenesis

Project Summary The human centromere contains non-coding repetitive alpha-satellite DNA sequences that is under active RNA polymerase (RNAP) II-catalyzed transcription. The centromeric transcription has been proposed to play an important role in the deposition of centromere proteins to centromeric chromatin and centromeric cohesion. However, these conclusions are facing a challenge because the approaches to suppress centromeric transcription in these studies were not specific to centromeres. Therefore, it is critically important to develop novel approaches to specifically inactivate centromeric transcription without significantly altering global gene transcription and then determine the functions of centromeric transcription. In addition, how centromeric transcription is regulated is also poorly understood. The overall objective of this application is to determine the functioning mechanisms underlying centromeric transcription. Based on the published and our preliminary data, we hypothesize that centromeric transcription orchestrated by specific factors and histone modifications during the cell cycle promotes centromeric cohesion that is essential for chromosome segregation. This hypothesis will be tested by pursuing three specific aims: 1) determining the functions of centromeric transcription. We will examine centromeric cohesion when centromeric transcription is specifically suppressed using our newly developed approach. 2) elucidating the epigenetic regulation of centromeric transcription. We will test the role of the histone mark H3K4 di-methylation (me2) in centromeric transcription and its regulation. 3) identifying the key regulators for centromeric transcription. We will test the functioning mechanism of Cyclin-dependent kinase (Cdk)11 in centromeric transcription. At the completion of the proposed research, we will expect to have determined the functioning mechanisms of centromeric transcription. These results will have an important positive impact because they will contribute to a conceptual framework for the future identification and development for potential cancer therapeutic targets.

项目摘要 人类中心包含在下面 活性RNA聚合酶（RNAP）II催化转录。中心转录已经 提议在丝粒蛋白的沉积中发挥重要作用 和丝粒凝聚力。但是，这些结论正面临挑战，因为这些方法是 在这些研究中抑制中心粒转录不是对centromeres的特异性。因此，是 开发新的方法以特异性灭活丝粒转录至关重要 没有显着改变全局基因转录，然后确定丝粒的功能 转录。此外，如何调节中心粒转录也很少了解。这 该应用的总体目的是确定centrymeric的功能机制 转录。根据已发布的和我们的初步数据，我们假设该层层 通过特定因素和组蛋白修饰在细胞周期中精心策划的转录促进 对染色体分离至关重要的丝粒凝聚力。该假设将通过 追求三个具体目标：1）确定丝粒转录的功能。我们将检查 当我们新的新近抑制中心粒转录时，丝粒内聚力 开发的方法。 2）阐明丝粒转录的表观遗传调节。我们将测试 组蛋白标记H3K4二甲基化（ME2）在丝粒转录及其调节中的作用。 3）识别丝粒转录的关键调节剂。我们将测试 Cyclin依赖性激酶（CDK）11中的丝粒转录。拟议完成时 研究，我们将期望确定着丝粒转录的功能机制。 这些结果将产生重要的积极影响，因为它们将有助于概念 潜在癌症治疗靶标的未来鉴定和开发框架。