Regulation of Archaeal Transcription

古菌转录的调控

• 批准号: 10622479
• 负责人: Thomas James Santangelo
• 金额: $ 38万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622479
• 关键词: Acceleration; Address; Architecture; Attention; Chromatin; Chromatin Structure; Complex; DNA Binding; DNA-Directed RNA Polymerase; Development; Disease; Eukaryotic Cell; Gene Expression; Gene Expression Regulation; Genetic Transcription; Genome; Goals; Histones; Human; Knowledge; Malignant Neoplasms; Molecular; Regulation; Research; Role; System; Transcription Elongation; Transcriptional Regulation; Variant; combat; genome-wide; transcription factor; transcription termination

Project Summary/Abstract The essential multi-subunit RNA polymerases are regulated at each stage of the transcription cycle to control gene expression in each Domain. In many cases the rate limiting step of gene expression is during transcription elongation, but major knowledge gaps remain in our understanding of post-initiation regulation of transcription. Our studies directly address outstanding questions of transcription regulation in archaeal and eukaryotic cells. Our overarching goals are to establish molecular mechanisms that regulate post-initiation activities of RNAP, and establish the regulation imposed by histone-based chromatin on gene expression. How does altering the chromatin-landscape alter gene expression? How, in molecular detail, do factors that modify the activities of RNA polymerase accelerate transcription on histone-bound DNA? How can the otherwise extremely stable transcription elongation complex be disrupted to terminate transcription accurately? These complex challenges demand continued attention to define the foundational mechanisms underlying gene expression and the aberrant gene expression associated with disease states and cancer. We defined that archaeal transcription and chromatin systems are closely related, yet minimal versions of the component complex eukaryotic transcription systems. We have described the complete archaeal transcription cycle and defined three mechanisms that control transcription termination decisions, each of which reveals similarities with bacterial and eukaryotic termination mechanisms and demands continued experimentation to delineate conserved mechanisms to disrupt the transcription elongation complex. Our understanding of how chromatin structure regulates gene expression is also incomplete. We will leverage the simplicity of single-histone chromatin formed with native histones and histone-variants to establish the regulation imposed by extended chromatin structures on a genome-wide level. We will also describe the molecular activities of conserved archaeal-eukaryotic transcription factors that modify RNA polymerase and accelerate transcription through histone-bound DNA.

项目总结/摘要 在转录的每个阶段，必需的多亚基RNA聚合酶都受到调节 循环以控制每个结构域中的基因表达。在许多情况下，基因的限速步骤 表达是在转录延伸，但主要的知识差距仍然在我们的研究中。 理解转录起始后的调节。我们的研究直接针对 在古细菌和真核细胞转录调控的突出问题。我们 总体目标是建立调节启动后活动的分子机制 的RNAP，并建立调控施加的组蛋白为基础的染色质对基因 表情改变染色质景观如何改变基因表达？如何在 分子的细节，做因素，修改活动的RNA聚合酶加速转录 组蛋白结合的DNA为什么在其他方面极其稳定的转录延伸 复合体被破坏以准确地终止转录？这些复杂的挑战要求 继续关注基因表达的基本机制， 与疾病状态和癌症相关的异常基因表达。 我们认为古细菌的转录和染色质系统是密切相关的， 组成复杂真核转录系统的版本。我们已经描述了 完整的古细菌转录周期，并确定了控制转录的三种机制 终止决定，其中每一个都揭示了与细菌和真核生物的相似之处， 终止机制，并要求继续实验，以划定保守的 破坏转录延伸复合物的机制。我们了解如何 染色质结构调节基因表达也是不完整的。我们将利用 由天然组蛋白和组蛋白变体形成的单组蛋白染色质的简单性， 在全基因组水平上建立由延伸的染色质结构施加的调节。我们 还将描述保守的古-真核转录因子的分子活性 其修饰RNA聚合酶并通过组蛋白结合DNA加速转录。