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Transcriptional coactivators showing physical and functional interactions with PPARγ include the protein acetyl transferase p300, the TRAP/Mediator complex that interacts with the general transcription machinery, and the highly regulated PGC-1α. We show that PGC-1α directly interacts with TRAP/Mediator, through the PPARγ-interacting subunit TRAP220, and stimulates TRAP/Mediator-dependent function on DNA templates. Further, while ineffective by itself, PGC-1α stimulates p300-dependent histone acetylation and transcription on chromatin templates in response to PPARγ. These functions are mediated by largely independent PPARγ, p300, and TRAP220 interaction domains in PGC-1α, whereas p300 and TRAP220 show ligand-dependent interactions with a common region of PPARγ. Apart from showing PGC-1α functions both in chromatin remodeling and in preinitiation complex formation or function (transcription), these results suggest a key role for PGC-1α, through concerted but dynamic interactions, in coordinating these steps. [Copyright &y& Elsevier]

Summary: Human TRAP/Mediator is a key coactivator for many transcription factors that act through direct interactions with distinct subunits, and MED1/TRAP220 is the main subunit target for various nuclear receptors. Remarkably, the current study shows that MED1/TRAP220 only exists in a TRAP/Mediator subpopulation (less then 20% of the total) that is greatly enriched in specific TRAP/Mediator subunits and is tightly associated with a near stoichiometeric level of RNA polymerase II. Importantly, this MED1/TRAP220-containing holoenzyme supports both basal- and activator-dependent transcription in an in vitro system lacking additional RNA polymerase II. Furthermore, chromatin immunoprecipitation experiments demonstrate an activator-selective recruitment of MED1/TRAP220-containing versus MED1/TRAP220-deficient TRAP/Mediator complexes to estrogen receptor (ER) and p53 target genes, respectively. Finally, RNAi studies show that MED1/TRAP220 is required for ER-mediated transcription and estrogen-dependent breast cancer cell growth. These observations have significant implications for our current understanding of the composition, heterogeneity, and functional specificity of TRAP/Mediator complexes. [Copyright &y& Elsevier]