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Open Access Research

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

Tanja Prenzel1, Frank Kramer2, Upasana Bedi13, Sankari Nagarajan13, Tim Beissbarth2 and Steven A Johnsen13*

Author Affiliations

1 Department of Molecular Oncology, Göttingen Center for Molecular Biosciences, University Medical Center Göttingen, Ernst-Caspari-Haus, Justus-von-Liebig-Weg 11, Göttingen 37077, Germany

2 Department of Medical Statistics, University Medical Center Göttingen, Humboldt Allee 32, Göttingen, 37073, Germany

3 Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, Hamburg 20246, Germany

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Epigenetics & Chromatin 2012, 5:13  doi:10.1186/1756-8935-5-13

Published: 22 August 2012

Abstract

Background

In 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.

Results

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.

Conclusions

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.

Keywords:
Estrogen receptor; Cohesin; Mediator; Chromatin