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

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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).