Using Mathematical Modelling to Deconstruct Transcription

使用数学模型解构转录

• 批准号: BB/S009035/1
• 负责人: Jane Mellor
• 金额: $ 86.18万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FS009035%2F1
• 关键词: Using; Mathematical; Modelling; Deconstruct; Transcription; Using; Mathematical; Modelling; Deconstruct; Transcription

Transcription is the first step in the complex process of gene expression that brings the characteristics of a cell into being, by transcribing the DNA code of genes into RNA copies, transcripts, which will subsequently be translated into proteins, the workhorses of a cell. As such, transcription is a highly regulated process that when disrupted can cause disease. Thus, there is a real need to understand all aspects of transcriptional regulation and exactly where and how it can go wrong.The best-known regulators of transcription are the DNA binding transcription factors which were thought to act as on/off switches for transcription by RNA polymerase. However, recent data suggests that many transcription factors do not act as the decision point for simply switching a gene on or off but at various stages following the start of transcription, during transcription elongation. Indeed, we have recently shown that the amount of the accessory factors associated with RNA polymerase, known as transcription elongation factors, is determined by the DNA-bound transcription factors, and that this differs on individual genes and with environmental conditions.In order to explore the various stages of transcription, and the impact of transcription factors on these events, we have developed a mathematical model that is trained on experimental data and can determine which of the many stages of transcription changes with mutation or environmental variation. We have begun the process of extending the model by including further details of the transcriptional process and training it on experimental data from humans and yeast, so that it can be applied generally. The purpose of this work to develop the model and exploit its predictive power so that we can describe the key steps at which the transcription of a gene is regulated and how this is likely to change when conditions change. The results of our modelling will enable us to move to a better understanding of how transcription is disrupted when environmental conditions change, when organisms are stressed and in disease where it may well identify potential therapeutic targets. We intend that the model becomes widely dispersed in the academic community.

转录是基因表达复杂过程的第一步，它通过将基因的DNA代码转录为RNA拷贝，转录本，将细胞的特征带入存在，随后将其转化为蛋白质，即细胞的工作马。因此，转录是一个高度调节的过程，当受到干扰会导致疾病。因此，真正需要了解转录调控的各个方面，以及确切的何处以及如何出现问题。转录的最著名调节剂是DNA结合转录因子，被认为是RNA聚合酶转录的开/关开关。但是，最近的数据表明，许多转录因子不是简单地打开或关闭基因的决策点，而是在转录伸长期间的转录开始后的各个阶段。实际上，我们最近表明，与RNA聚合酶（称为转录伸长因子）相关的辅助因子的数量由DNA结合的转录因子确定，并且这种因素在单个基因和环境状态上不同，以探索转录的各种阶段，以及转录因素对这些事件的影响，我们已经开发了许多数学模型，我们可以在许多模型中进行培训，并且在实验中培训了一点点，并且在实验中进行了培训，并且在实验中进行了培训，并且在实验中培训了一定的实验，并且有效的实验培训了，这些模型的变化因素是培训的，该模型的相互作用是在探索转录因素的变化因素，并且可以通过实验进行培训。环境变化。我们已经开始通过包括转录过程的更多细节并根据人类和酵母的实验数据进行培训，从而扩展了该模型，以便将其普遍应用。这项工作的目的是开发模型并利用其预测能力，以便我们可以描述调节基因转录的关键步骤，以及当条件发生变化时，这可能会发生变化。我们的建模结果将使我们能够更好地了解当环境条件发生变化，强调生物时以及在疾病中可能识别潜在的治疗靶标时的转录如何中断。我们打算在学术界广泛分散该模型。