p300 requires its histone acetyltransferase activity and SRC-1 interactiondomain to facilitate thyroid hormone receptor activation in chromatin

We have characterized the mechanism by which coactivator p300 facilitates t ranscriptional activation mediated by the heterodimer of thyroid hormone (T 3) receptor and 9-cis retinoid acid receptor (TR-RXR) in the context of chr omatin, We demonstrate that, while p300 can enhance the transcriptional act ivation mediated by both liganded TR-RXR and GAL4-VP16, its histone acetylt ransferase activity (HAT) is required for its ability to facilitate ligande d TR-RXR- but not GAL4-VP16-mediated transcriptional activation, To underst and how p300 is recruited by liganded TR-RXR, we have analyzed the interact ions between TR-RXR and p300 as well as SRC-1 family coactivators, We show that, in contrast to a strong hormone-dependent interaction between TR-RXR and SRC-1 family coactivators, p300 displays minimal, if any, T3-dependent interaction with TR-RXR, However, p300 can be recruited by liganded TR-RXR through its interaction with SRC-1 family coactivators, Consistent with the protein-protein interaction profile described above, we demonstrate that t he SRC-1 interaction domain of p300 is important for its ability to facilit ate transcriptional activation mediated by TR-RXR, whereas its nuclear rece ptor interaction domain is dispensable. Collectively, these results reveal the functional significance of the HAT activity of p300 and define an indir ect mode for the action of p300 in TR-RXR activation.