Mechanisms of RNAPII transcription regulation by the Mediator complex kinase subunit, Cdk8

生物体经常受到它们所处环境变化的挑战。要想在这些侮辱中幸存下来，他们需要做出适当的回应。基因的激活和抑制是生物体对环境做出反应的关键机制。这是通过一个称为转录的过程中的变化来实现的。转录是由一种名为RNA聚合酶II(RNAPII)的分子机器执行的，该机器读取细胞DNA中编码的信息。转录过程是复杂的，它需要数百种被称为转录因子的调节因子的集体作用，这些调控因子的功能是根据环境信号将RNAPII引向或远离DNA的特定区域。CDK8是一种已知的转录因子调节因子，因此，它在调节生物体对环境变化的反应能力方面发挥着重要作用。尽管CDK8很重要，但我们对它的功能和自身的调控知之甚少，特别是对环境信号的反应。一些证据表明，CDK8可能比我们目前所知的调控更多的转录因子。事实上，我们最近发现CDK8调节一种转录因子，该转录因子控制新陈代谢基因的激活，以响应营养信号。在研究转录的最新发现和专业知识的坚实基础上，这项建议将调查CDK8如何调节转录以响应环境。我们将通过回答三个具体的问题来做到这一点：1)CDK8在什么条件下调节代谢基因的表达，它到底是如何做到这一点的？2)CDK8是否调节其他转录因子的活性，从而控制转录对环境的响应？3)CDK8本身是如何对环境信号做出调节的？总而言之，这项工作将揭示生物体对环境侮辱的反应和生存机制的重要方面。总体而言，发现转录调控的新原则对于了解这一过程是如何工作的以及为什么它经常在疾病(例如癌症、自身免疫和发育障碍)中改变至关重要。

Organisms are regularly challenged by changes to the environments they inhabit. Surviving these insults requires them to mount an appropriate response. Gene activation and repression is a key mechanism by which organisms respond to their environments. This is achieved through changes in a process called transcription. Transcription is performed by a molecular machine called RNA Polymerase II (RNAPII) which reads information encode in the cell's DNA. The process of transcription is complex, it requires the collective action of hundreds of regulators, known as transcription factors, that function to direct RNAPII towards or away from specific regions of the DNA in response to environmental signals. Cdk8 is a known regulator of transcription factors and as such, it plays important roles in mediating the ability of organisms to respond to changes in their environment. Despite its importance, we know very little about how Cdk8 functions and is itself regulated, particularly in response to environmental signals. Several lines of evidence suggest that Cdk8 likely regulates more transcription factors than we currently are aware of. In fact, we recently discovered that Cdk8 regulates a transcription factor that controls the activation of metabolism genes in response to nutrient signals. Building on a solid foundation of recent findings and expertise in studying transcription, this proposal will investigate how Cdk8 regulates transcription in response to the environment. We will do this by answering three specific questions: 1) Under what conditions does Cdk8 regulate the expression of metabolism genes and how exactly does it do this? 2) Does Cdk8 modulate the activity of other transcription factors that control transcription in response to the environment? 3) How is Cdk8 itself regulated in response to environmental signals? Collectively, this work will reveal important aspects of the mechanisms by organisms respond and survive environmental insults. Overall, uncovering new principles of transcription regulation is critical to understanding how this process works and why it is often altered in disease (e.g. cancer, autoimmunity, and developmental disorders).