Functions and Regulation of Centromeric Transcription

着丝粒转录的功能和调控

基本信息

批准号：
10379263
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
项目类别：
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/10379263
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 Methylation Mission Mitosis Mitotic Outcome Pathway interactions 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

项目摘要

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.

项目概要人类着丝粒含有非编码重复 α 卫星 DNA 序列，该序列位于活性 RNA 聚合酶 (RNAP) II 催化的转录。着丝粒转录为被认为在着丝粒蛋白沉积到着丝粒染色质中发挥重要作用和着丝粒凝聚力。然而，这些结论面临着挑战，因为方法这些研究中抑制着丝粒转录的方法并非针对着丝粒。因此，它是开发特异性失活着丝粒转录的新方法至关重要不显着改变全局基因转录，然后确定着丝粒的功能转录。此外，人们对着丝粒转录如何调控也知之甚少。这本申请的总体目标是确定着丝粒的功能机制转录。根据已发表的数据和我们的初步数据，我们假设着丝粒细胞周期中特定因子和组蛋白修饰协调的转录促进着丝粒内聚力对于染色体分离至关重要。这个假设将被检验追求三个具体目标：1）确定着丝粒转录的功能。我们将检查当使用我们的新方法特异性抑制着丝粒转录时，着丝粒凝聚力开发的方法。 2）阐明着丝粒转录的表观遗传调控。我们将测试组蛋白标记 H3K4 二甲基化 (me2) 在着丝粒转录及其调控中的作用。 3）确定着丝粒转录的关键调控因子。我们将测试其运作机制着丝粒转录中的细胞周期蛋白依赖性激酶 (Cdk)11。在完成拟议的通过研究，我们期望能够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，因为它们将有助于形成概念性的未来识别和开发潜在癌症治疗靶点的框架。