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

Abstract

Gene expression results from the coordinated actions of transcription factor proteins and coregulators. Estrogen receptor alpha (ER␣) is a ligand-activated transcription factor that can both activate and repress the expression of genes. Activation of transcription by estrogen-bound ER␣ has been studied in detail, as has antagonist-induced repression, such as that which occurs by tamoxifen. How estrogen-bound ER␣ represses gene transcription remains unclear. In this report, we identify a new mechanism of estrogen-induced transcriptional repression by using the ER␣ gene, ESR1. Upon estrogen treatment, ER␣ 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␣-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␣ is identified. These data support a model of repression wherein actions of ER␣ and Sin3A at the proximal promoter can overcome activating signals at distal or proximal sites and ultimately decrease gene expression.Downregulation of receptors by their ligands is a fundamental process by which cells control sensitivity to stimuli. For steroid hormones, this involves lipophilic ligands binding to intracellular receptors to induce a decline in receptor number. Regulation of estrogen (E2) receptor alpha (ER␣) by E2 is one example. The E2-induced decline in ER␣ is, in part, mediated through direct regulation of the protein. It is well documented that decreases in ER␣ protein levels in response to E2 occur via the ubiquitin-proteasome pathway (1, 42). The mRNA levels of ER␣ also decrease, but the mechanism responsible for E2-induced repression of the ER␣ gene, ESR1, is not established (5, 49, 52).ER␣ is a ligand-activated transcription factor that mediates the effects of E2 by regulating gene expression. Activation by ER␣ has been studied in detail, but little is understood about how E2-bound ER␣ represses transcription. E2-induced repression is, however, of significant biological importance. Microarray analyses of E2-treated breast cancer cell lines show that the number of repressed genes is greater than or near the number of activated genes (10,19,29,32). Yet, there are limited reports investigating E2-induced repression, and no generalized mechanism has emerged (6,13,22,25,43,47,59,60,71,74). Antagonistinduced repression by selective ER modulators involves conformational changes that prevent coactivator binding to ER␣ (55). Such a conformational blockade does not occur with agonist binding and thus cannot account for E2-induced gene repression.Many repressive complexes exist to restrict gene expression in response to cellular signals. One example is the Sin3 complex, which was identified in yeast but is conserved in mammals (41, ...

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