The Mediator complex in thyroid hormone receptor action.

BACKGROUND: Mediator is an evolutionarily conserved multisubunit complex that plays an essential regulatory role in eukaryotic transcription of protein-encoding genes. The human complex was first isolated as a transcriptional coactivator bound to the thyroid hormone receptor (TR) and has since been shown to play a key coregulatory role for a broad range of nuclear hormone receptors (NRs) as well as other signal-activated transcription factors. SCOPE OF REVIEW: We provide a general overview of Mediator structure and function, summarize the mechanisms by which Mediator is targeted to NRs, and outline recent evidence revealing Mediator as a regulatory axis for other distinct coregulatory factors, chromatin modifying enzymes and cellular signal transduction pathways. MAJOR
CONCLUSIONS: Besides serving as a functional interface with the RNA polymerase II basal transcription machinery, Mediator plays a more versatile role in regulating transcription including the ability to: a) facilitate gene-specific chromatin looping events; b) coordinate chromatin modification events with preinitiation complex assembly; and c) regulate critical steps that occur during transcriptional elongation. The variably associated MED1 subunit continues to emerge as a pivotal player in Mediator function, not only as the primary interaction site for NRs, but also as a crucial interaction hub for other coregulatory factors, and as an important regulatory target for signal-activated kinases. GENERAL SIGNIFICANCE: Mediator plays an integral coregulatory role at NR target genes by functionally interacting with the basal transcription apparatus and by coordinating the action of chromatin modifying enzymes and transcription elongation factors. This article is part of a Special Issue entitled Thyroid hormone signalling.