Regulation of Archaeal Transcription

古菌转录的调控

• 批准号: 10324749
• 负责人: Thomas James Santangelo
• 金额: $ 36.37万
• 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/10324749
• 关键词: Address; Architecture; Attention; Chromatin; Chromatin Structure; Complex; DNA Binding; DNA-Directed RNA Polymerase; Development; Disease; Eukaryotic Cell; Foundations; Gene Expression; Gene Expression Regulation; Genetic Transcription; Genome; Goals; Histones; Human; Knowledge; Malignant Neoplasms; Molecular; Regulation; Research; Role; System; Transcription Elongation; Transcriptional Regulation; Variant; base; 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.

项目摘要/摘要 在转录的每个阶段调节必需的多亚基RNA聚合酶 循环控制每个结构域中的基因表达。在许多情况下，基因的速率限制步骤 表达在转录伸长率期间，但主要的知识差距仍然存在于我们的 了解转录后调节调节。我们的研究直接解决 古细胞和真核细胞中转录调控的杰出问题。我们的 总体目标是建立分子机制来调节生产后活动 RNAP的of，并建立基于组蛋白的染色质对基因施加的调节 表达。改变染色质 - 景观如何改变基因表达？如何，在 分子细节，执行修饰RNA聚合酶活性加速转录的因素 在组蛋白结合的DNA上？原本非常稳定的转录伸长率如何 复杂被破坏以准确终止转录吗？这些复杂的挑战需求 继续关注以定义基因表达的基本机制和 与疾病状态和癌症相关的异常基因表达。 我们定义了古细菌转录和染色质系统密切相关，但很少 组件复杂的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定义了控制转录的三种机制 终止决策，每个决定都揭示了与细菌和真核的相似之处 终止机制和需求继续实验以划定保守的 破坏转录伸长复合物的机制。我们对如何的理解 调节基因表达的染色质结构也不完整。我们将利用 由天然组蛋白和组蛋白变异形成的单螺旋染色质的简单性 在全基因组水平上建立由扩展的染色质结构施加的调节。我们 还将描述保守的古核转录因子的分子活性 这可以修饰RNA聚合酶并通过结合组蛋白结合的DNA加速转录。