Estrogen Receptor Alpha Represses Transcription of Early Target Genes via p300 and CtBP1

The regulation of gene expression by nuclear receptors controls the phenotypic properties and diverse biologies of target cells. In breast cancer cells, estrogen receptor alpha (ER alpha) is a master regulator of transcriptional stimulation and repression, yet the mechanisms by which agonist-bound ER alpha elicits repression are poorly understood. We analyzed early estrogen-repressed genes and found that ER alpha is recruited to ER alpha binding sites of these genes, albeit more transiently and less efficiently than for estrogen-stimulated genes. Of multiple cofactors studied, only p300 was recruited to ER alpha binding sites of repressed genes, and its knockdown prevented estrogen-mediated gene repression. Because p300 is involved in transcription initiation, we tested whether ER alpha might be trying to stimulate transcription at repressed genes, with ultimately failure and a shift to a repressive program. We found that estrogen increases transcription in a rapid but transient manner at early estrogen-repressed genes but that this is followed by recruitment of the corepressor CtBP1, a p300-interacting partner that plays an essential role in the repressive process. Thus, at early estrogen-repressed genes, ER alpha initiates transient stimulation of transcription but fails to maintain the transcriptional process observed at estrogen-stimulated genes; rather, it uses p300 to recruit CtBP1-containing complexes, eliciting chromatin modifications that lead to transcriptional repression.