Expression levels of estrogen receptor beta are modulated by components of the molecular clock.
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 (ERbeta) is, together with ERalpha, 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 ERbeta, but not ERalpha, is controlled by circadian clock proteins. We show that ERbeta 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 ERbeta expression is exerted through a conserved E-box element in the ERbeta 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 ERbeta.
Cai
Wen
W
Department of Biosciences and Nutrition, Karolinska Institute, S-141 57 Huddinge, Sweden.
Rambaud
Juliette
J
Teboul
Michèle
M
Masse
Ingrid
I
Benoit
Gerard
G
Gustafsson
Jan-Ake
JA
Delaunay
Franck
F
Laudet
Vincent
V
Pongratz
Ingemar
I
D056930:ARNTL Transcription Factors; D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002940:Circadian Rhythm; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008168:Lung / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D056950:Period Circadian Proteins; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D016415:Sequence Alignment; D017385:Sequence Homology; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins; D047629:Estrogen Receptor beta; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D015534:Trans-Activators; C538960:BMAL1 protein, human; C538961:Bmal1 protein, mouse; C539022:PER1 protein, human; C539023:Per1 protein, mouse; C538943:CLOCK protein, human; C538944:Clock protein, mouse