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

Abstract

BackgroundIn conjunction with posttranslational chromatin modifications, proper arrangement of higher order chromatin structure appears to be important for controlling transcription in the nucleus. Recent genome-wide studies have shown that the Estrogen Receptor-alpha (ERα), encoded by the ESR1 gene, nucleates tissue-specific long-range chromosomal interactions in collaboration with the cohesin complex. Furthermore, the Mediator complex not only regulates ERα activity, but also interacts with the cohesin complex to facilitate long-range chromosomal interactions. However, whether the cohesin and Mediator complexes function together to contribute to estrogen-regulated gene transcription remains unknown.ResultsIn 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.ConclusionsThese 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.

MED12 protein expression in breast fibroepithelial lesions: correlation with mutation status and oestrogen receptor expression

“…This is consistent with findings by Prenzel et al ,5 where ERα expression was impaired when MED12 was knocked down in breast cancer cell lines. However, in the stromal component, we observed no ERα expression in all cases except for the single fibroadenoma with smooth muscle metaplasia, even if the tumours expressed MED12 protein.…”

“…Besides, the mediator complex is also an essential coactivator for a broad range of nuclear hormone receptors 4. Prenzel et al 5 reported a decrease in oestrogen receptor α (ERα) protein levels and a significant impairment to oestrogen-regulated transcriptome following knockdown of the MED12 gene in MCF7 breast cancer cell lines 5. Kang et al 6 demonstrated that the mediator complex interacts directly with ERα and ERβ and enhances receptor function in vitro .…”

The emerging role of mediator complex subunit 12 in tumorigenesis and response to chemotherapeutics

“…Recently, it was found that MED12 colocalizes on the ERα ( ESR1 ) gene with the cohesion subunit SMC3. The occupancy of either subunit across the ESR1 gene depends on the other, and both are required for RNAPII–mediated transcriptional initiation, suggesting that high‐order chromatin architecture controlled by MED12 and cohesin may be exploited for the regulation of ER expression and the treatment of estrogen‐dependent breast cancer . However, control of ER expression and ER‐regulated transcription in ER‐driven malignancies is far more complex and has been elegantly reviewed by others .…”

“…The occupancy of either subunit across the ESR1 gene depends on the other, and both are required for RNAPII-mediated transcriptional initiation, suggesting that high-order chromatin architecture controlled by MED12 and cohesin may be exploited for the regulation of ER expression and the treatment of estrogen-dependent breast cancer. 48 However, control of ER expression and ER-regulated transcription in ER-driven malignancies is far more complex and has been elegantly reviewed by others. 49,50 Liu and colleagues recently reported that MED12 interacts with the JmjC-domaincontaining protein (JMJD6) and recruits JMJD6 to the active enhancers bound by ERα, releasing paused RNA polymerase on cognate estrogen target genes.…”

Systematic identification of Ctr9 regulome in ERα-positive breast cancer

“…For example, loss-of-function approach coupled with gene expression microarray profiling demonstrated that BRD4, KDM3A, and Cohesin are required for the expression of a large portion of ERα target genes [18, 40–42]. GATA3 and FOXA1 have been implied as the pioneer factors for priming the genome-wide distribution of ERα [36, 39].…”