Yin and yang of mediator function revealed by human mutants

Mediator is an ∼30-subunit multiprotein complex approximately twice the size of the 12-subunit RNA polymerase (i.e., RNA polymerase II [Pol II]) that transcribes most human genes. Mediator functions as a molecular bridge between Pol II bound at transcription start sites (TSSs) and activation and repression domains of regulatory sequence-specific DNA binding transcription factors (TFs) bound to enhancers and promoter proximal transcription control sequences (1⇓⇓⇓–5) (Fig. 1). In PNAS, Zhou et al. (6) report a significant advance in understanding how mutations in one Mediator subunit, MED12, result in two types of X-linked intellectual disability known as FG and Lujan syndromes. Studies of the mutant Mediators reveal how MED12 interactions with different components of the transcriptional machine produce opposing activating and inhibitory influences necessary for the proper level of transcription required for normal development.