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.

转录调节是细胞编排单个基因或基因组的表达的手段。对单个细胞的最新研究表明，在大多数情况下，转录不是连续的活性，而是发生在爆发中。每个基因产生的RNA量与此类爆发的幅度和频率直接成正比。如何控制这两个参数并不完全清楚，但是看来启动子的DNA序列信息决定了幅度，而爆发频率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节元件。它们的主要作用是募集酶（聚合酶）和其他关键蛋白（转录因子，激活剂和抑制剂），以打开DNA螺旋并阅读遗传信息。启动子和增强剂的另一个重要特征是，要正常运作，它们必须处于近距离状态或彼此接触。这个财政年度，我们的实验室探讨了细胞如何促进调节DNA之间的接触以推动转录。 我们在该领域的主要出版物： 1- El Khattabi等。细胞，2019年8月。在此手稿中，我们表明，一种称为介体的大型复合物将RNA聚合酶募集到哺乳动物细胞中的基因启动子。一旦在启动子开始，调解人就会发生急剧的结构变化（可能是通过与转录因子相关联），在酵母中驱动聚合酶的磷酸化，这是转录必不可少的活性。最后，与当前的模型相反，我们发现启动子和增强子的束缚并不是必需的。因此，新发现阐明了在较高生物体中如何调节转录的方式。