Cohesin is required for expression of the estrogen receptor-alpha (ESR1) gene

In this study we show that depletion of the cohesin subunit SMC3 or the Mediator subunit MED12 significantly impairs the ERα-regulated transcriptome. Surprisingly, SMC3 depletion appears to elicit this effect indirectly by rapidly decreasing ESR1 transcription and ERα protein levels. Moreover, we provide evidence that both SMC3 and MED12 colocalize on the ESR1 gene and are mutually required for their own occupancy as well as for RNAPII occupancy across the ESR1 gene. Finally, we show that extended proteasome inhibition decreases the mRNA expression of cohesin subunits which accompanies a decrease in ESR1 mRNA and ERα protein levels as well as estrogen-regulated transcription.These results identify the ESR1 gene as a cohesin/Mediator-dependent gene and indicate that this regulation may potentially be exploited for the treatment of estrogen-dependent breast cancer.Transcriptional control is a highly ordered and complex process involving interactions between various transcription factors and the transcriptional apparatus [1]. Importantly, changes in chromatin organization, including post-translational histone modifications and higher order chromatin structure direct transcriptional activity and control gene expression patterns [2,3]. Recent studies have begun to uncover the complexity of interactions between different chromatin loci on a genome-wide level [4-6].The estrogen receptor-alpha (ERα) is a ligand-activated transcription factor which plays an essential role in directing tissue-specific gene expression [7]. Importantly, ERα is a primary target for anti-estrogen therapy in breast cancer and its presence is a prognostic marker for patient outcome [7,8]. Interfering with distinct aspects of ERα-regulated transcription may provide novel therapeutic options for the treatment of ERα-positive breast cancer [9]. During gene transcription ERα functions not only to recruit an intricate network of transcriptional coregulators, but also nucleates long-range chromosomal int