As gene-specific transcription factors, nuclear receptors are broadly involved in many important biological processes. Their function on target genes requires the stepwise assembly of different coactivator complexes that facilitate chromatin remodeling and subsequent preinitiation complex (PIC) formation and function. Mediator has proved to be a crucial, and general, nuclear receptor-interacting coactivator, with demonstrated functions in transcription steps ranging from chromatin remodeling to subsequent PIC formation and function. Here we discuss our current understanding of (i) pathways involved in Mediator recruitment and function through nuclear receptor target gene enhancers and promoters, (ii) conditional requirements for the strong nuclear receptor-Mediator interactions mediated by NR AF2 domains and the MED1 LXXLL motifs, (iii) Mediator functions, through different nuclear receptor-interacting subunits, in different metabolic pathways, (iv) emerging functions of Mediator as a corepressor in addition to its major role as a coactivator and (v) mechanisms by which Mediator acts to transmit signals from enhancer-bound nuclear receptors to the general transcription machinery at core promoters to effect PIC formation and function. As a nuclear receptor coregulator with increasingly diverse functions, Mediator may thus modulate nuclear receptor signaling through several different mechanisms.
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