Protein SUMOylation and transcriptional control in a dynamic 3D chromatin environment

动态 3D 染色质环境中的蛋白质 SUMO 化和转录控制

基本信息

批准号：
BB/V000403/1
负责人：
Andrew Sharrocks
金额：
$ 81.8万
依托单位：
University of Manchester
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FV000403%2F1
关键词：
Protein SUMOylation transcriptional control dynamic

项目摘要

The decoding of our genome through the process of gene transcription ultimately dictates the form and activity of the cells in our body. Importantly, this decoding activity is not static but is dynamic and changes in response to intra and extracellular cues. These dynamic responses are controlled by pathways such as the ERK signalling cascade which ultimately impact on gene expression profiles. This pathway is important for normal cellular responses in our immune systems and brains, which enables us to function normally in combatting microbial infections and process information. Once deregulated, this pathway can lead to disease states, as exemplified by its frequent hyperactivation in cancer. Our preliminary work has shown that the target genes for this pathway exist in complex 3-dimensional environments, whereby multiple control elements cluster together. Furthermore, we demonstrate that these control elements are marked by a protein called SUMO and that this modification is dynamically deposited across genes as transcription proceeds. This is suggestive of an important role for SUMO. In this project we will examine the role of SUMO in inducible gene regulation. First we will assess the role of SUMO in creating a local 3D structure that facilitates gene expression. Next we will ask how SUMO effects gene activation and determine relevant target proteins that are involved in this process. This will enable us to understand how the switches that control gene transcription are regulated. This is important, not only in the context of ERK pathway signalling but more broadly as SUMO has been shown to play a critical role in cell fate decisions, which is of particular relevance in iPS cell generation which are the building blocks used in regenerative medicine.

通过基因转录过程对我们的基因组进行解码最终决定了我们体内细胞的形式和活动。重要的是，这种解码活动不是静态的，而是动态的，并且响应细胞内和细胞外的线索而变化。这些动态反应由 ERK 信号级联等途径控制，最终影响基因表达谱。该途径对于我们的免疫系统和大脑中的正常细胞反应非常重要，它使我们能够正常地对抗微生物感染和处理信息。一旦解除管制，该途径可能导致疾病状态，其在癌症中频繁过度激活就是例证。我们的初步工作表明，该途径的靶基因存在于复杂的三维环境中，多个控制元件聚集在一起。此外，我们证明这些控制元件由一种称为 SUMO 的蛋白质标记，并且随着转录的进行，这种修饰动态地沉积在基因中。这表明 SUMO 的重要作用。在这个项目中，我们将研究 SUMO 在诱导基因调控中的作用。首先，我们将评估 SUMO 在创建促进基因表达的局部 3D 结构中的作用。接下来我们将询问 SUMO 如何影响基因激活并确定参与此过程的相关靶蛋白。这将使我们能够了解控制基因转录的开关是如何被调节的。这不仅在 ERK 通路信号传导的背景下很重要，而且在更广泛的范围内，SUMO 已被证明在细胞命运决定中发挥着关键作用，这与 iPS 细胞的生成特别相关，而 iPS 细胞是再生医学中使用的构建模块。