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Patrick Müller Department of Biosciences and Nutrition, Department of Microbiology and Molecular Biology, Karolinska Institutet, Novum, S-141 57 Huddinge, Sweden

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Kenneth W Merrell Department of Biosciences and Nutrition, Department of Microbiology and Molecular Biology, Karolinska Institutet, Novum, S-141 57 Huddinge, Sweden

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Justin D Crofts Department of Biosciences and Nutrition, Department of Microbiology and Molecular Biology, Karolinska Institutet, Novum, S-141 57 Huddinge, Sweden

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Caroline Rönnlund Department of Biosciences and Nutrition, Department of Microbiology and Molecular Biology, Karolinska Institutet, Novum, S-141 57 Huddinge, Sweden

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Chin-Yo Lin Department of Biosciences and Nutrition, Department of Microbiology and Molecular Biology, Karolinska Institutet, Novum, S-141 57 Huddinge, Sweden

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Jan-Åke Gustafsson Department of Biosciences and Nutrition, Department of Microbiology and Molecular Biology, Karolinska Institutet, Novum, S-141 57 Huddinge, Sweden

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Anders Ström Department of Biosciences and Nutrition, Department of Microbiology and Molecular Biology, Karolinska Institutet, Novum, S-141 57 Huddinge, Sweden

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Regulation of hairy and enhancer of split homologue-1 (HES-1) by estradiol and all-trans retinoic acid affects proliferation of human breast cancer cells. Here, we identify and characterize cis-regulatory elements involved in HES-1 regulation. In the distal 5′ promoter of the HES-1 gene, we found a retinoic acid response element and in the distal 3′ region, an estrogen receptor α(ER)α binding site. The ERα binding site, composed of an estrogen response element (ERE) and an ERE half-site, is important for both ERα binding and transcriptional regulation. Chromatin immunoprecipitation assays revealed that ERα is recruited to the ERE and associates with the HES-1 promoter. We also show recruitment of nuclear receptor co-regulators to the ERE in response to estradiol, followed by a decrease in histone acetylation and RNA polymerase II docking in the HES-1 promoter region. Our findings are consistent with a novel type of repressive estrogen response element in the distal 3′ region of the HES-1 gene.

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