Understanding the role of nuclear myosin in the spatial organisation of transcription

了解核肌球蛋白在转录空间组织中的作用

• 批准号: BB/X008460/1
• 负责人: Christopher Toseland
• 金额: $ 64.02万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX008460%2F1
• 关键词: Understanding; role; nuclear; myosin; spatial

The regulation of gene expression is essential for healthy living. Gene expression is one of the most fundamental processes in biology. In eukaryotic cells, RNA polymerase II (RNAPII) directs the flow of genetic information from DNA to mRNA. Detailed genetic and biochemical assays have revealed a multi-level regulation of transcription, including the general transcription factors, activators and repressors. This occurs both distal and proximal to the gene through physical interactions.A cell's response to stimulus requires coordinated and efficient regulation of many genes. While it is widely accepted there is temporal regulation of gene expression, more recently there has been an increase in reports proposed spatial regulation. The spatial organization of transcription has been debated and studied for over three decades. The formation of RNAPII clusters enables distal genomic contacts while increasing the local concentration of enzymes, which enhances efficiency. We have identified the actin-based molecular motor, myosin VI, as a critical regulator of this spatial organisation with respect to transcription initiation. Our previous work has revealed that myosin VI directly binds RNAPII and it can bind DNA. Our current work has revealed that myosin VI has the ability to aid the organisation of transcription initiation by holding RNAPII at transcription sites. The loss of inhibition of myosin VI ATPase activity leads to disruption of RNAPII organisation and a reduction in gene expression.We now wish to understand how myosin VI is regulated in this role and how widespread this effect is throughout the transcription cycle (e.g. during elongation). These findings will be fundamental for understanding the spatial organisation of transcription and how perturbation may occur during disease and aging. This may also reveal routes for developing therapeutic strategies.We will perform this work using state-of-the-art single molecule imaging techniques. This interdisciplinary approach will allow us to directly address how regulation of myosin VI related to gene expression.

基因表达的调控对健康生活至关重要。基因表达是生物学中最基本的过程之一。在真核细胞中，RNA聚合酶II （RNAPII）指导遗传信息从DNA到mRNA的流动。详细的遗传和生化分析揭示了转录的多层次调控，包括一般转录因子，激活因子和抑制因子。这通过物理相互作用发生在基因的远端和近端。细胞对刺激的反应需要许多基因的协调和有效的调节。虽然人们普遍认为基因表达存在时间调控，但最近提出空间调控的报道有所增加。转录的空间组织已经争论和研究了三十多年。RNAPII簇的形成使远端基因组接触成为可能，同时增加了酶的局部浓度，从而提高了效率。我们已经确定了基于肌动蛋白的分子马达，肌凝蛋白VI，作为这种空间组织的关键调节因子，涉及转录起始。我们之前的工作表明，肌凝蛋白VI直接结合RNAPII，它可以结合DNA。我们目前的工作表明，肌凝蛋白VI具有通过在转录位点保持RNAPII来帮助组织转录起始的能力。肌球蛋白VI atp酶活性抑制的丧失导致RNAPII组织的破坏和基因表达的减少。我们现在希望了解肌凝蛋白VI是如何在这种作用中受到调节的，以及这种作用在整个转录周期（例如在伸长期间）中有多普遍。这些发现将是理解转录的空间组织以及在疾病和衰老期间如何发生扰动的基础。这也可能揭示开发治疗策略的途径。我们将使用最先进的单分子成像技术来完成这项工作。这种跨学科的方法将使我们能够直接解决肌球蛋白VI的调控如何与基因表达相关。