Repression of ESR1 through Actions of Estrogen Receptor Alpha and Sin3A at the Proximal Promoter

Gene expression results from the coordinated actions of transcription factor proteins and coregulators. Estrogen receptor alpha (ER alpha) is a ligand-activated transcription factor that can both activate and repress the expression of genes. Activation of transcription by estrogen-bound ER alpha has been studied in detail, as has antagonist-induced repression, such as that which occurs by tamoxifen. How estrogen-bound ER alpha represses gene transcription remains unclear. In this report, we identify a new mechanism of estrogen-induced transcriptional repression by using the ER alpha gene, ESR1. Upon estrogen treatment, ER alpha is recruited to two sites on ESR1, one distal (ENH1) and the other at the proximal (A) promoter. Coactivator proteins, namely, p300 and AIB1, are found at both ER alpha-binding sites. However, recruitment of the Sin3A repressor, loss of RNA polymerase II, and changes in histone modifications occur only at the A promoter. Reduction of Sin3A expression by RNA interference specifically inhibits estrogen-induced repression of ESR1. Furthermore, an estrogen-responsive interaction between Sin3A and ER alpha is identified. These data support a model of repression wherein actions of ER alpha and Sin3A at the proximal promoter can overcome activating signals at distal or proximal sites and ultimately decrease gene expression.