Transcriptional regulation by Mediator subunit MED12 (Schrewe lab)

Transcription factors require coactivators to communicate with the general transcription machinery and ensure that biological inputs are translated into specific gene-expression programs. Central among these coactivators is the evolutionarily highly conserved Mediator that functions as a molecular bridge between transcription factors bound at enhancers and the polymerase machinery. Mediator is a large macromolecular complex and arranged in 4 modules: head, middle, tail and kinase module. Various subunits of Mediator are required for the interaction with specific transcription factors; thereby the complex can sense and integrate a multitude of signals and delivers a properly calibrated output to RNA polymerase II. Particularly the kinase module has been recently implicated in various diseases and in cancer. Specifically, the kinase module member MED12 has been found mutated in malignant and benign tumors, as well as in various intellectual disability syndromes. To elucidate whether specific signaling pathways rely on MED12 to recruit Mediator or whether MED12 is actually required in a more general fashion to regulate transcription, we generated various Med12 mouse models. Absence of Med12 causes embryonic arrest at day 7.5. To clarify the functions of Med12 at later stages of development and in specific cells and tissues, we are using our conditional Med12 mouse line and crossing it to tissue-specific and inducible Cre-deleter lines. This strategy allows one to bypass early mortality and still facilitates the study of the fate of different Med12-deficient somatic cells. We are currently studying the role of Med12 in neural crest cells and in limb mesenchymal cells, since inactivation of Med12 in these cells leads to the absence of peripheral neurons or the deficiency of chondrogenesis, respectively. In a different approach, we are expressing epitope-tagged Med12 in ES cells and mice to improve our searches to detect novel protein-protein and protein-RNA interactions.

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