Mediator's Kinase Module: A Modular Regulator of Cell Fate

Selective gene expression is crucial in maintaining the self-renewing and multipotent properties of stem cells. Mediator is a large, evolutionarily conserved, multi-subunit protein complex that modulates gene expression by relaying signals from cell type-specific transcription factors to RNA polymerase II. In humans, this complex consists of 30 subunits arranged in four modules. One critical module of the Mediator complex is the kinase module consisting of four subunits: MED12, MED13, CDK8, and CCNC. The kinase module exists in variable association with the 26-subunit Mediator core and affects transcription through phosphorylation of transcription factors and by controlling Mediator structure and function. Many studies have shown the kinase module to be a key player in the maintenance of stem cells that is distinct from a general role in transcription. Genetic studies have revealed that dysregulation of this kinase subunit contributes to the development of many human diseases. In this review, we discuss the importance of the Mediator kinase module by examining how this module functions with the more recently identified transcriptional super-enhancers, how changes in the kinase module and its activity can lead to the development of human disease, and the role of this unique module in directing and maintaining cell state. As we look to use stem cells to understand human development and treat human disease through both cell-based therapies and tissue engineering, we need to remain aware of the on-going research and address critical gaps in knowledge related to the molecular mechanisms that control cell fate.