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Molecular and Cellular Biology, January 2008, p. 784-793, Vol. 28, No. 2
0270-7306/08/$08.00+0     doi:10.1128/MCB.00233-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Expression Levels of Estrogen Receptor β Are Modulated by Components of the Molecular Clock{triangledown}

Wen Cai,1 Juliette Rambaud,2 Michèle Teboul,3 Ingrid Masse,2 Gerard Benoit,2 Jan-Åke Gustafsson,1 Franck Delaunay,3 Vincent Laudet,2 and Ingemar Pongratz1*

Karolinska Institutet, Department of Biosciences and Nutrition, S-141 57 Huddinge, Sweden,1 Université de Lyon, Institut de Génomique Fonctionnelle de Lyon, Molecular Zoology team, Ecole Normale Supérieure de Lyon, Université Lyon 1, CNRS, INRA, Institut Fédératif 128 Biosciences Gerland Lyon Sud, Lyon, France,2 Laboratoire de Physiologie Cellulaire et Moleculaire, Université de Nice-Sophia-Antipolis, CNRS, 28 Avenue Valrose, 06108 Nice, France3

Received 8 February 2007/ Returned for modification 9 March 2007/ Accepted 22 October 2007

Circadian regulation of gene expression plays a major role in health and disease. The precise role of the circadian system remains to be clarified, but it is known that circadian proteins generate physiological rhythms in organisms by regulating clock-controlled target genes. The estrogen receptor beta (ERβ) is, together with ER{alpha}, a member of the nuclear receptor superfamily and a key mediator of estrogen action. Interestingly, recent studies show that disturbed circadian rhythmicity in humans can increase the risk of reproductive malfunctions, suggesting a link between the circadian system and ER-mediated transcription pathways. Here, we identify a novel level of regulation of estrogen signaling where ERβ, but not ER{alpha}, is controlled by circadian clock proteins. We show that ERβ mRNA levels fluctuate in different peripheral tissues following a robust circadian pattern, with a peak at the light-dark transition, which is maintained under free-running conditions. Interestingly, this oscillation is abolished in clock-deficient BMAL1 knockout mice. Circadian control of ERβ expression is exerted through a conserved E-box element in the ERβ promoter region that recruits circadian regulatory factors. Furthermore, using small interfering RNA-mediated knockdown assays, we show that the expression levels of the circadian regulatory factors directly influence estrogen signaling by regulating the intracellular levels of endogenous ERβ.

* Corresponding author. Mailing address: Department of Biosciences and Nutrition, Karolinska Institute, S-141 57 Huddinge, Sweden. Phone: 46 8 6089113. Fax: 46 8 7745538. E-mail: inpo{at}biosci.ki.se

{triangledown} Published ahead of print on 26 November 2007.

Molecular and Cellular Biology, January 2008, p. 784-793, Vol. 28, No. 2
0270-7306/08/$08.00+0     doi:10.1128/MCB.00233-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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