Molecular mechanism of the recruitment of SWI/SNF chromatin remodeling complex and histone acetyltransferase to estrogen-responsive promoters

Estrogen receptor alpha (ER) is a member of the family of nuclear receptors and functions as a transcriptional factor to induce gene expression by binding to specific DNA sequences upon hormone treatment. It regulates cell growth, development and metabolic homeostasis in multi-cellular organisms. Estrogen-mediated transcription has been intensively studied genome-wide as well as on a small number of specific endogenous target promoters. However, the exact mechanism by which ER coordinates the activities of chromatin remodeling complexes and coactivators to facilitate initiation of transcription remains elusive. Here, we show the molecular mechanisms of the recruitment of the SWI/SNF chromatin remodeling complex by Fli-I, and recruitment of Tip60, a histone acetyltransferase.;Fli-I can bind directly to both ER and BAF53, an actin-related component of the SWI/SNF complex, suggesting that Fli-I may recruit SWI/SNF to ER target genes via interaction with BAF53. Depletion of endogenous Fli-I or BAF53 specifically eliminated part of the complex cyclical pattern of recruitment of SWI/SNF to estrogen-responsive promoters in a way that indicates multiple roles and multiple mechanisms of recruitment for SWI/SNF in estrogen-dependent target gene expression.;Tip60 interacts with ER in a hormone dependent manner, and point mutation of a leucine-rich motif reduced Tip60 promoter occupancy at an estrogen-regulated promoter. Tip60 also interacts with methylated histone H3K4 in vitro and the depletion of endogenous BRG1 also impairs Tip60 recruitment significantly but not completely. These findings suggest a role for chromatin remodeling by SWI/SNF complex followed by possible binding of Tip60 to methylated histones during the transcription initiation process. These results suggest three steps that may contribute to Tip60 recruitment and occupancy on estrogen-regulated promoters: (1) chromatin remodeling by SWI/SNF; (2) interaction with ER; and (3) binding to methylated histones.;These results begin to establish the functional relationships and interdependencies that coordinate the actions of the many coactivators participating in the transcriptional activation process.