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Nature reviews: Molecular cell biology

The Mediator complex as a master regulator of transcription by RNA polymerase II

Sidharth Sirdeshmukh

Research Associate, Dewpoint

The Mediator complex is basically a central regulator/ coordinating scaffold for enhancers that beckons Pol II to transcribe DNA to RNA, but doesn’t bind to DNA itself. I think of it as a rotating log that floats around, but doesn’t touch the DNA. This log has peg holes, and the peg holes can change size and position, leaving room for various enhancers (the pegs). The size and position of the peg holes will continue to change as new enhancers bind. When the peg holes are filled ‘favorably’ then Pol II is finally recruited to the DNA, initiating transcription. This review says that the Mediator complex is composed of protein modules that are flexible, and that the flexibility (ie. Peg holes that change size and position) is conferred by the IDRs within those modules. Transcription factors also have IDRs, particularly in the regions where they bind the Mediator. So, to go back to the log analogy, the pegs and the logs physically diffuse and concentrate between/ among each other. Some of theoretical open questions that Mediator IDRs suggest will be closed as better crystal structures of the Mediator complex and its modules are resolved and made available. Condensate biologists may also link colocalization/ kinetics experiments to transcriptional regulation experiments to say more about this. What’s interesting to me at this point, is the matrix representation of transcription and translation that one can picture: The Mediator-directed ‘scaffold’ exists around DNA and drives the production of RNA, which now either degrades, remains, or is translated into protein. These newly translated proteins may serve as enhancers themselves, now circling back to regulate the Mediator complex from which they came from. The cell is basically a meshwork/ soup/ jungle of RNA and protein that comes together and separates in real time, in response to unique cellular contexts. The Mediator complex encourages/ directs this cyclical cascade of RNA-protein interactions that support cells. What’s interesting to consider is whether Mediators in separate cells are ‘aware’ of each other, and coordinate processes to support neighboring cells? If these processes are coordinated through cells, are they coordinated to support the health of the cells, or the health of the Mediators themselves? Perhaps there are peripheral RNAs or proteins in the same cell, or neighboring cells, that are modulating the group-conformation of the Mediators within single cells or across microenvironments? Is there a way that diffusing the Mediator complex (or modules within it), which is highly disordered and displays a condensate phenotype according to this review, in one cell type, would produce favorable effects in a heterogenous environment?