Mechanisms of gene expression

基因表达机制

• 批准号: 10006384
• 负责人: rafael c casellas
• 金额: $ 473.18万
• 依托单位: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10006384
• 关键词: Architecture; Area; Biological Assay; CRISPR/Cas technology; Cells; Complex; Cryoelectron Microscopy; DNA; DNA Sequence; DNA-Directed RNA Polymerase; Enhancers; Enzymes; Frequencies; Gene Expression; Genes; Genetic Screening; Genetic Transcription; Human Genome; Individual; Laboratories; Light; Mammalian Cell; Manuscripts; Mediator of activation protein; Microscopy; Modeling; Nuclear; Organism; Phosphorylation; Polymerase; Proteins; Publications; RNA; Regulator Genes; Regulatory Element; Resolution; Role; Structure; System; Technology; Transcriptional Regulation; Yeasts; comparative genomics; genetic information; inhibitor/antagonist; mouse genome; neural network; promoter; recruit; transcription factor

Transcriptional regulation is the means whereby cells orchestrate expression of individual genes or group of genes. Recent studies with single cells have shown that, for the most part, transcription is not a continuous activity but it occurs in bursts. The amount of RNA produced for each gene is directly proportional to the amplitude and frequency of such bursts. How these two parameters are controlled is not totally clear, but it appears that DNA sequence information at promoters determine the amplitude, while burst frequencies rely on sequence information at enhancers. Promoters and enhancers are also known as gene regulatory elements. their primary role is to recruit enzymes (polymerases) and other key proteins (transcription factors, activators and inhibitors) that open up the DNA helix and read the genetic information. Another important feature of promoters and enhancers is that to function properly they must either be in close proximity or in contact with each other. This fiscal year, our laboratory has explored how the cell facilitate contacts between regulatory DNA to drive transcription. Our key publication in this area: 1- El Khattabi et al. Cell, August 2019. In this manuscript we have shown that a large complex known as Mediator recruits RNA polymerases to gene promoters in mammalian cells. Once at promoters, Mediator undergoes a drastic structural change (probably by associating with transcription factors) which in yeast drives phosphorylation of polymerases, an activity essential for transcription. Finally, contrary to current models, we have found that Mediator is not required for the tethering of promoters and enhancers. The new findings therefore shed light on how transcription is regulated in higher organisms.

转录调控是细胞协调单个基因或基因组表达的手段。最近对单细胞的研究表明，在大多数情况下，转录不是连续的活动，而是突然发生的。每个基因产生的 RNA 量与这种爆发的幅度和频率成正比。如何控制这两个参数尚不完全清楚，但似乎启动子处的 DNA 序列信息决定了幅度，而突发频率则依赖于增强子处的序列信息。启动子和增强子也称为基因调控元件。它们的主要作用是招募酶（聚合酶）和其他关键蛋白质（转录因子、激活剂和抑制剂）来打开 DNA 螺旋并读取遗传信息。启动子和增强子的另一个重要特征是，为了正常发挥作用，它们必须彼此靠近或接触。本财年，我们的实验室探索了细胞如何促进调控 DNA 之间的接触以驱动转录。 我们在该领域的主要出版物： 1-埃尔·哈塔比等人。 Cell，2019 年 8 月。在这篇手稿中，我们展示了一种称为 Mediator 的大型复合物将 RNA 聚合酶募集到哺乳动物细胞中的基因启动子上。一旦到达启动子，介体就会经历剧烈的结构变化（可能是通过与转录因子结合），在酵母中，这种变化会驱动聚合酶的磷酸化，这是转录所必需的活性。最后，与当前模型相反，我们发现启动子和增强子的束缚不需要介体。因此，这些新发现揭示了高等生物中转录是如何调控的。