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-Regulated Gene Transcription, Supporting a "Ying Yang" Relationship between ER and ERß in Mice
Division of Endocrinology (M.K.L., S.M., S.S., C.O.), Department of Internal Medicine, Sahlgrenska University Hospital, S-41345 Gothenburg, Sweden; and Department of Medical Nutrition and Department of BioSciences (J.-Å.G., H.G., K.D.-W.), Karolinska Institute, Novum, S-14157 Huddinge, Sweden
Address all correspondence and requests for reprints to: Claes Ohlsson, Professor, Department of Internal Medicine, Division of Endocrinology, RCEM, Sahlgrenska University Hospital, S-41345 Gothenburg, Sweden. E-mail: claes.ohlsson{at}medic.gu.se.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
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(ER)-regulated gene transcription in bone. The average stimulatory effect of estrogen on estrogen-regulated bone genes in ER-inactivated mice was intermediate between that seen in WT and ERß double-inactivated mice. Thus, ERß inhibits ER-mediated gene transcription in the presence of ER, whereas, in the absence of ER, it can partially replace ER. In conclusion, our in vivo data indicate that an important physiological role of ERß is to modulate ER-mediated gene transcription supporting a "Ying Yang" relationship between ER and ERß in mice. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
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+/+ß-/- mice (BERKO) have an increased amount of cortical bone and are partly protected against age-related trabecular bone loss that normally occurs in old female wild-type (WT) mice. Therefore, one may speculate that ERß represses the bone-protective effect of estrogen mediated via estrogen receptor- (ER) (1, 2, 3). A possible interaction between ER and ERß in the regulation of transcriptional activity has previously been investigated in different in vitro systems. It is clear that ERß and ER can form heterodimeric complexes with retained DNA-binding ability (4). Transient transfection assays have demonstrated that ERß has the capacity to repress the transcriptional activity of ER (5, 6). Furthermore, when complexed with estradiol, ER and ERß signal in opposite directions from an activator protein 1 site (7). An inhibitory effect of ERß might be explained by the finding that ERß does not contain a strong activation function 1 within its amino terminus but, rather, contains a repressor domain; when this particular segment is removed, the overall transcriptional activity of the receptor increases (6). Thus, previous in vitro data indicate that ERß can sometimes act as a dominant negative regulator of ER activity. Gene expression profiling opens up possibilities to investigate the interplay between ER and ERß in a global sense. The aim of the present study was to determine, in vivo, the role of ERß and its possible interactions with ER in global estrogen-regulated transcriptional activity in bone. |
RESULTS AND DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
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-Regulated Gene Transcription in Bone and Liver, is generally not required for estrogen-regulated gene transcription in bone. The relative magnitude of the effect of estrogen in WT and BERKO mice was compared for these genes. Interestingly, the average stimulatory effect of estrogen on the expression of these genes was 85% higher in BERKO than in WT mice and, when considering the individual genes, it was found that 80% of the genes were more regulated by estrogen in BERKO than in WT mice (Fig. 1A
and Table 1). ER mRNA levels in bone were unchanged in 3-month-old estrogen-treated female BERKO mice compared with WT mice (WT, 100 ± 13%, BERKO, 132 ± 29% of WT mice, n = 7–8) as determined by real-time PCR.
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and Table 1). As a negative control, we compared the expression of all genes not regulated by estrogen (n = 9060) without finding any difference between WT and BERKO mice (data not shown). The stimulatory effect of estrogen on the expression of 13 genes in bone and 8 genes in liver was confirmed by real-time PCR analysis (Fig. 2 and data not shown). Thus, in the presence of ER, it is clear that ERß reduces the global estrogen-stimulated gene transcription in bone and liver. This is the first demonstration that ERß is a global inhibitor of ER-regulated gene transcription in mice. In contrast, a minority of the estrogen-regulated genes were more regulated in WT than in BERKO mice, which might indicate that ERß has an additional role as a potent activator of a small specific gene set. However, we believe, rather, that these results represent a random distribution of several estrogen-regulated genes, where most genes are more regulated and very few are less regulated in BERKO than in WT mice.
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-repressing effect of ERß on transcriptional activity is supported by recent functional in vivo studies demonstrating that ERß represses some ER-mediated effects, including effects on female bone, thymus involution, fat reduction, and proliferative effects in uterus and prostate (8, 9).
The number of genes inhibited by estrogen in bone from both WT and BERKO mice was lower than the number of genes stimulated by estrogen (stimulated, 240; inhibited, 35). The average inhibitory effect of estrogen on these genes was more pronounced in BERKO compared with WT mice and, when considering the individual genes, it was found that 83% of the genes were more regulated by estrogen in BERKO than in WT mice (Fig. 1C and Table 1). The number of genes inhibited by estrogen in liver (n = 6) was too low to permit any statistical difference between WT and BERKO mice even though a similar tendency as in bone was found (Fig. 1D and Table 1). These data indicate that ERß, in the presence of ER, not only reduces the stimulatory but also the inhibitory effect of estrogen on gene transcription.
ERß Can Partially Replace ER in Estrogen-Regulated Gene Transcription
The function of ERß on estrogen-regulated gene transcription in the absence of ER was investigated by comparing the effect of estrogen in bone from ovx WT, ER-/-ß+/+ (ERKO), BERKO, and ER-/-ß-/- (DERKO) mice. We could, by microarray analysis, clearly demonstrate that more than 98% of the genes stimulated by estrogen in WT and BERKO mice were unchanged by estrogen in DERKO mice, demonstrating that, for most genes, either ER or ERß is required for the mediation of the effect of estrogen (Fig. 3). Less than 2% of the estrogen-regulated genes were regulated by estrogen also in DERKO mice, indicating that these few genes were regulated in an ER/ERß-independent manner, but one cannot exclude a minor ER activity remaining in these mice (10, 11). Alternatively, estrogen has been suggested to exert nongenomic actions via cell membrane receptors in a variety of cell types (12, 13, 14), and the effect might also be due to some low-affinity binding to other known nuclear receptors (14). Interestingly, the average stimulatory effect of estrogen in ERKO (176 ± 11% over vehicle) was intermediate between that seen in WT (275 ± 14% over vehicle) and DERKO (-7 ± 3% over vehicle) mice (Fig. 3).
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+ or -, ERß + or -) with gene as block effect, demonstrating that all these four groups are significantly different from each other (P < 0.00001). Similar results were also seen using three-way ANOVA applied on ranks within blocks, with gene as block effect (P < 0.00001). These data demonstrate that ERß, in the absence of ER, is able to partially mediate the effect of estrogen on gene transcription (Fig. 3). However, ER is more efficient than ERß in mediating the effect of estrogen on gene transcription. These analyses also demonstrated that there is a clear negative interaction between the effect of ER and ERß, which could be interpreted as meaning that ERß significantly reduces the stimulatory effect of ER (Figs. 3 and 4). Thus, ERß inhibits ER-mediated gene transcription in the presence of ER, whereas it can partially replace ER in the absence of ER (Fig. 4).
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and GRß), that one of these two subtypes can act as a dominant negative inhibitor of the transcriptional activity of the other subtype [PR-A inhibits PR-B and GRß inhibits GR (15, 16, 17)]. Our present in vivo study together with previous in vitro studies suggest that ER and ERß provide yet another example of two nuclear receptor subtypes that demonstrate distinct transcriptional activities. The contrasting transcriptional activities of the different subtypes of PR, GR, and ER indicate that the relative tissue distributions of receptor subtypes are a major determinant of the biological effects of their respective ligands.
The increased estrogen-regulated gene transcription in BERKO mice compared with WT mice might be explained by the fact that ERß is a transdominant repressor of ER. An alternative, and more probable, explanation is a competition between two activators, ER and ERß, which exhibit different intrinsic activities. A competition between the more active ER and the less active ERß in WT mice results in a reduced gene activation compared with the situation in BERKO mice where only the more active ER is present. The interesting finding that ERß can reduce the transcriptional activity of ER in vivo was, in the present study, obtained from two tissues, liver and bone, which both seem to be mainly ER controlled. In other tissues, including prostate, lung, and ovary, it is clear that ERß is a major regulator in its own right (8, 9, 18). Accordingly, we cannot extrapolate the present data to conclude, in general, that repression of ER is the major physiological function of ERß in all tissues.
In the present study, mice were treated for 3 wk with estradiol. Therefore, it is not clear which genes were directly transcriptionally regulated by estradiol and which genes were secondarily regulated by other genes regulated by estradiol. Furthermore, the microarray data do not distinguish between changes in transcription vs. changes in RNA processing or RNA stability. Thus, the present result should be interpreted as the net result of estrogen on mRNA levels after chronic estradiol treatment.
In conclusion, our data indicate that an important role of ERß is to modulate ER-mediated gene transcription in bone and liver, supporting a "Ying Yang" relationship between ER and ERß in mice.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
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+/-ß+/-) mice were mated with female double-heterozygous (ER+/-ß+/-) mice, resulting in ER+/+ß+/+ (WT), ER-/-ß+/+ (ERKO), ER+/+ß-/- (BERKO), and ER-/-ß-/- (DERKO) offspring (20, 21, 22). The diet, housing, and genetic background were as previously described (22). The mice were ovx at 2 months of age. Ovaries were removed after a flank incision and the incisions were closed with metallic clips. After recovery for 4 d, mice were injected sc with 2.3 µg/mouse/d of 17ß-estradiol benzoate (Sigma, St. Louis, MO) for 5 d/wk during a 3-wk period. Control mice received injections of vehicle oil (olive oil, Apoteksbolaget, Gothenburg, Sweden). The study protocol was reviewed and approved by the ethical committee at the University of Gothenburg.
DNA Microarray Analysis
RNA from humerus (n = 6: WT vehicle, DERKO estrogen; n = 7: WT estrogen; n = 8: BERKO vehicle, BERKO estrogen; n = 4: DERKO vehicle; n = 3: ERKO vehicle, ERKO estrogen) and liver (n = 6: WT vehicle, WT estrogen, BERKO vehicle, BERKO estrogen, DERKO vehicle and DERKO estrogen; n = 4: ERKO vehicle, ERKO estrogen) were prepared as described elsewhere (23). The RNA was further purified using RNeasy Kit (QIAGEN, Chatsworth, CA). For microarray assays the RNA samples were divided into two pools per animal group, whereas for the confirmatory real-time PCR analysis each individual animal was analyzed separately. The pooled RNA was reverse transcribed into cDNA, labeled, and analyzed by DNA microarray (MG-U74A Array; Affymetrix, Santa Clara, CA). The array represents approximately 5700 characterized mouse genes and approximately 3700 uncharacterized expressed sequence tags (ESTs) (in total, 9400). In the present article we do not distinguish between characterized mouse genes and uncharacterized ESTs. Preparation of labeled cRNA and hybridization was done according to the Affymetrix Gene Chip Expression Analysis manual.
Bioinformatics
Scanned output files were analyzed using Affymetrix Micro Array Suite Version 4.0.1 software. To allow comparison of gene expression, both between groups and between tissues, the GeneChips were globally scaled to an average intensity of 500. The estrogen-regulated genes were determined by calculating the fold change in average between vehicle-treated and estrogen-treated samples. Comparisons were made between the two vehicle-treated and the two estrogen-treated GeneChips, generating a total of four comparisons. We defined very strict criteria for genes to be regarded as regulated; 1) the absolute call for the gene had to be present (i.e. regarded by the software to be expressed at a detectable level; Affymetrix Micro Array Suite Version 4.0.1) for all GeneChips; 2) at least three of the four comparisons had to be considered increased (I) or decreased (D) according to Affymetrix algorithms; 3) the average fold increase or decrease of the four comparisons should be at least 2.0-fold. Thus, we may have excluded some estrogen-regulated genes but this was done to avoid false positives among the regulated genes. The average coefficient of variation for the four microarray comparisons was 22.8% for the 240 estrogen-regulated genes in bone.
For determination of the ER specificity of the genes regulated by estrogen in WT mice, the same rules as above were applied for comparisons between vehicle and estrogen-treated ERKO, BERKO, and DERKO GeneChips.
Real-Time PCR Analysis
The confirmatory real-time PCR analyses were, as described in the microarray section, run on each individual sample. The analyses were performed using the ABI Prism 7700 Sequence Detection System (PE Applied Biosystems, Stockholm, Sweden) using probes labeled with the reporter fluorescent dye FAM. Predesigned primers and a probe labeled with the reporter fluorescent dye VIC, specific for 18S rRNA, were included in the reactions as an internal standard. The oligonucleotide primers and probes were purchased from PE Applied Biosystems. The cDNA was amplified at the following conditions: 1 cycle at 50 C for 2 min and 95 C for 10 min, followed by 40 cycles at 95 C for 15 sec and 60 C for 1 min. The mRNA amount of each gene was calculated using the Standard Curve Method (multiplex reaction, following the instructions in User Bulletin no. 2, PE Applied Biosystems) and adjusted for the expression of 18S rRNA.
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FOOTNOTES |
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Abbreviations: BERKO, ER+/+ß-/-; DERKO, ER-/-ß-/-; ER, estrogen receptor; ERKO, ER-/-ß++; EST, expressed sequence tag; GR, glucocorticoid receptor; ovx, ovariectomized; PR, progesterone receptor; WT, wild-type.
Received for publication June 5, 2002. Accepted for publication October 30, 2002.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
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, ß and double knockouts reveals a dual role for ERß in bone remodelling. J Bone Miner Res 15:1088
. Mol Endocrinol 11:1486–1496 transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens. Endocrinology 140:5566–5578 and ERß at AP1 sites. Science 277:1508–1510 in the uterus. Proc Natl Acad Sci USA 97:5936–5941 may be dispensable to mediate the effect of estradiol on endothelial NO production in mice. Proc Natl Acad Sci USA 99:2205–2210(q/11) and gß
proteins and membrane signaling of calcitriol and estradiol. J Cell Biochem 75:138–146[CrossRef][Medline]
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 T. Pelzer, P.-A. A. Loza, K. Hu, B. Bayer, C. Dienesch, L. Calvillo, J. F. Couse, K. S. Korach, L. Neyses, and G. Ertl Increased Mortality and Aggravation of Heart Failure in Estrogen Receptor-{beta} Knockout Mice After Myocardial Infarction Circulation, March 29, 2005; 111(12): 1492 - 1498. [Abstract] [Full Text] [PDF]
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A. E. Kudwa, C. Bodo, J.-A. Gustafsson, and E. F. Rissman A previously uncharacterized role for estrogen receptor {beta}: Defeminization of male brain and behavior PNAS, March 22, 2005; 102(12): 4608 - 4612. [Abstract] [Full Text] [PDF]
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 S. H. Kim, A. Tamrazi, K. E. Carlson, and J. A. Katzenellenbogen A Proteomic Microarray Approach for Exploring Ligand-initiated Nuclear Hormone Receptor Pharmacology, Receptor Selectivity, and Heterodimer Functionality Mol. Cell. Proteomics, March 1, 2005; 4(3): 267 - 277. [Abstract] [Full Text] [PDF]
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 L. Gennari, D. Merlotti, V. De Paola, A. Calabro, L. Becherini, G. Martini, and R. Nuti Estrogen Receptor Gene Polymorphisms and the Genetics of Osteoporosis: A HuGE Review Am. J. Epidemiol., February 15, 2005; 161(4): 307 - 320. [Abstract] [Full Text] [PDF]
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M. Skavdahl, C. Steenbergen, J. Clark, P. Myers, T. Demianenko, L. Mao, H. A. Rockman, K. S. Korach, and E. Murphy Estrogen receptor-{beta} mediates male-female differences in the development of pressure overload hypertrophy Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H469 - H476. [Abstract] [Full Text] [PDF]
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Y. Yamamoto, J. Shibata, K. Yonekura, K. Sato, A. Hashimoto, Y. Aoyagi, K. Wierzba, S. Yano, T. Asao, A. U. Buzdar, et al. TAS-108, a Novel Oral Steroidal Antiestrogenic Agent, Is a Pure Antagonist on Estrogen Receptor {alpha} and a Partial Agonist on Estrogen Receptor {beta} with Low Uterotrophic Effect Clin. Cancer Res., January 1, 2005; 11(1): 315 - 322. [Abstract] [Full Text] [PDF]
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S. Rodriguez-Cuenca, M. Monjo, A. M. Proenza, and P. Roca Depot differences in steroid receptor expression in adipose tissue: possible role of the local steroid milieu Am J Physiol Endocrinol Metab, January 1, 2005; 288(1): E200 - E207. [Abstract] [Full Text] [PDF]
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 M. H. Herynk and S. A. W. Fuqua Estrogen Receptor Mutations in Human Disease Endocr. Rev., December 1, 2004; 25(6): 869 - 898. [Abstract] [Full Text] [PDF]
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A. van de Stolpe, A. J. Slycke, M. O. Reinders, A. W. M. Zomer, S. Goodenough, C. Behl, A. F. Seasholtz, and P. T. van der Saag Estrogen Receptor (ER)-Mediated Transcriptional Regulation of the Human Corticotropin-Releasing Hormone-Binding Protein Promoter: Differential Effects of ER{alpha} and ER{beta} Mol. Endocrinol., December 1, 2004; 18(12): 2908 - 2923. [Abstract] [Full Text] [PDF]
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G. M. Leong, S. Moverare, J. Brce, N. Doyle, K. Sjogren, K. Dahlman-Wright, J.-A. Gustafsson, K. K. Y. Ho, C. Ohlsson, and K.-C. Leung Estrogen Up-Regulates Hepatic Expression of Suppressors of Cytokine Signaling-2 and -3 in Vivo and in Vitro Endocrinology, December 1, 2004; 145(12): 5525 - 5531. [Abstract] [Full Text] [PDF]
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P. Yang, J. Wang, Y. Shen, and S. K. Roy Developmental Expression of Estrogen Receptor (ER) {alpha} and ER{beta} in the Hamster Ovary: Regulation by Follicle-Stimulating Hormone Endocrinology, December 1, 2004; 145(12): 5757 - 5766. [Abstract] [Full Text] [PDF]
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A Bardin, N Boulle, G Lazennec, F Vignon, and P Pujol Loss of ER{beta} expression as a common step in estrogen-dependent tumor progression Endocr. Relat. Cancer, September 1, 2004; 11(3): 537 - 551. [Abstract] [Full Text] [PDF]
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A. Bardin, P. Hoffmann, N. Boulle, D. Katsaros, F. Vignon, P. Pujol, and G. Lazennec Involvement of Estrogen Receptor {beta} in Ovarian Carcinogenesis Cancer Res., August 15, 2004; 64(16): 5861 - 5869. [Abstract] [Full Text] [PDF]
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A. Hillisch, O. Peters, D. Kosemund, G. Muller, A. Walter, B. Schneider, G. Reddersen, W. Elger, and K.-H. Fritzemeier Dissecting Physiological Roles of Estrogen Receptor {alpha} and {beta} with Potent Selective Ligands from Structure-Based Design Mol. Endocrinol., July 1, 2004; 18(7): 1599 - 1609. [Abstract] [Full Text] [PDF]
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D. Vanderschueren, L. Vandenput, S. Boonen, M. K. Lindberg, R. Bouillon, and C. Ohlsson Androgens and Bone Endocr. Rev., June 1, 2004; 25(3): 389 - 425. [Abstract] [Full Text] [PDF]
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 C. Martin, M. Ross, K. E. Chapman, R. Andrew, P. Bollina, J. R. Seckl, and F. K. Habib CYP7B Generates a Selective Estrogen Receptor {beta} Agonist in Human Prostate J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2928 - 2935. [Abstract] [Full Text] [PDF]
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 V. S. Melvin, C. Harrell, J. S. Adelman, W. L. Kraus, M. Churchill, and D. P. Edwards The Role of the C-terminal Extension (CTE) of the Estrogen Receptor {alpha} and {beta} DNA Binding Domain in DNA Binding and Interaction with HMGB J. Biol. Chem., April 9, 2004; 279(15): 14763 - 14771. [Abstract] [Full Text] [PDF]
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C. D. Toran-Allerand Minireview: A Plethora of Estrogen Receptors in the Brain: Where Will It End? Endocrinology, March 1, 2004; 145(3): 1069 - 1074. [Abstract] [Full Text] [PDF]
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M. Tena-Sempere, V.M. Navarro, A. Mayen, C. Bellido, and J.E. Sanchez-Criado Regulation of Estrogen Receptor (ER) Isoform Messenger RNA Expression by Different ER Ligands in Female Rat Pituitary Biol Reprod, March 1, 2004; 70(3): 671 - 678. [Abstract] [Full Text] [PDF]
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D. Liu, Z. Zhang, W. Gladwell, and C. T. Teng Estrogen Stimulates Estrogen-Related Receptor {alpha} Gene Expression through Conserved Hormone Response Elements Endocrinology, November 1, 2003; 144(11): 4894 - 4904. [Abstract] [Full Text] [PDF]
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A. L. Siebel, H. M. Gehring, I. G. T. Reytomas, and L. J. Parry Inhibition of Oxytocin Receptor and Estrogen Receptor-{alpha} Expression, But Not Relaxin Receptors (LGR7), in the Myometrium of Late Pregnant Relaxin Gene Knockout Mice Endocrinology, October 1, 2003; 144(10): 4272 - 4275. [Abstract] [Full Text] [PDF]
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 J. Matthews and J.-A. Gustafsson Estrogen Signaling: A Subtle Balance Between ER{alpha} and ER{beta} Mol. Interv., August 1, 2003; 3(5): 281 - 292. [Abstract] [Full Text] [PDF]
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J. Frasor, D. H. Barnett, J. M. Danes, R. Hess, A. F. Parlow, and B. S. Katzenellenbogen Response-Specific and Ligand Dose-Dependent Modulation of Estrogen Receptor (ER) {alpha} Activity by ER{beta} in the Uterus Endocrinology, July 1, 2003; 144(7): 3159 - 3166. [Abstract] [Full Text] [PDF]
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