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Department of Pathology (J.A.M., J.M.), Division of Laboratory Medicine, Department of Biomedical Engineering (L.C.), and Department of Genetics (G.D.S.), Washington University School of Medicine, St. Louis, Missouri 63110
Address all correspondence and requests for reprints to: Jeffrey Milbrandt, Department of Pathology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110. E-mail: jeff{at}pathbox.wustl.edu.
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Abstract |
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Introduction |
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An appreciation of the central role for AR in prostate physiology has motivated efforts on to identify direct AR target genes and characterize the mechanisms through which AR transactivates target promoters (3, 4, 5). Several important findings have emerged from these studies, including the identification of multiple coreceptor molecules that interact with AR at target cis-regulatory sites (6). For example, the transcriptional cofactors cAMP response element-binding protein (CBP), steroid receptor coactivator (SRC)-1 and p300/CBP-associated factor (PCAF), among others, have been shown to interact with AR at the prostate-specific antigen (PSA) promoter as well as an enhancer located approximately 4 kb upstream of the PSA gene (2, 7). These molecules each possess histone acetyl-transferase (HAT) activities that promote chromatin remodeling and increased PSA expression (2, 7, 8, 9, 10, 11). Histone modifications play a role in repression of the PSA gene as well. The AR antagonist bicalutamide leads to recruitment of the histone deacetylases nuclear receptor corepressor and silencing mediator of retinoid and thyroid receptors (7). Subsequent chromatin condensation results in repression of the PSA gene. Similar interactions have been demonstrated at the kallikrein-2 (KLK2) locus, and these observations establish a conceptual framework for understanding AR-mediated gene regulation (2).
One weakness of current AR transactivation models is that they are derived from experiments performed in cultured cells rather than in vivo. Furthermore, many previous studies of AR target elements have used promoter-reporter constructs that remove cis-regulatory elements from their in vivo chromosomal context. Whereas in vitro studies are inarguably useful and informative, it is nevertheless imperative that more substantial efforts be made to elucidate gene-regulatory interactions in the context of living animals. To this end, we sought to characterize the interactions among AR, its cofactors, and target cis-regulatory elements in the mouse prostate.
The object of studies presented herein is another androgen target, the FKBP5 gene. FKBP5 encodes a 51-kDa immunophilin that modulates the cytosolic vs. nuclear distribution of steroid hormone receptors (12, 13). Like the PSA and KLK2 genes, FKBP5 is rapidly up-regulated in cultured prostate cancer cells following androgen stimulation (14, 15, 16). However, unlike previously characterized AR targets, the FKBP5 locus lacks a consensus AR binding site in its proximal promoter. Furthermore, the FKBP5 expression pattern suggests a more complex cis-regulatory architecture than that of PSA and KLK2 because the FKBP5 gene product is expressed in nonprostatic tissues such as the spleen and the umbilical cord (17). Together, these properties made FKBP5 an attractive target for in vivo studies aimed at identifying of a novel enhancer, characterizing the transcription complexes that associate with the enhancer and evaluating enhancer function in nonprostatic tissues.
We localized AR binding to a distinct enhancer in the fifth intron of the FKBP5 gene. This enhancer demonstrates promiscuous responsiveness to AR, glucocorticoid receptor (GR), and progesterone receptor (PR) in vitro, but its in vivo function appears more limited because we were unable to identify interactions between the enhancer and steroid hormone receptors in nonprostatic tissues. In the mouse prostate, we found that AR selectively recruits CBP but not SRC-1 or PCAF to the distal FKBP5 enhancer element. In contrast to the PSA gene, the AR-CBP complex does not directly interact with basal transcription factors at the proximal promoter. Moreover, the HAT activity of the AR-CBP complex is confined to the distal enhancer because histone acetylation at the remainder of the locus, including the proximal promoter, is unaffected by testosterone deprivation. Thus, these data implicate an indirect communication between the distal, AR bound enhancer element and the proximal FKBP5 promoter. Such a regulatory mechanism has not been previously described for AR target genes, and these findings highlight a rich complexity within the cis- and trans-regulatory architecture of AR target genes that is difficult to appreciate in more limited, in vitro studies. Further in vivo analysis of AR target genes, including FKBP5, should offer valuable insights into prostate cancer pathogenesis and nuclear hormone receptor biology.
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Materials and Methods |
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Antibodies
Chromatin immunoprecipitation (ChIP) assays were performed using antibodies obtained from Upstate Biotechnology (Lake Placid, NY) (AR, acetyl histone H3) and Santa Cruz Biotechnology (Santa Cruz, CA) [polymerase II (PolII), GR, CBP, SRC-1]. The PCAF antibody was a generous gift from Y. Nakatani (Dana-Farber Cancer Institute, Boston, MA).
Quantitative ChIP
Chromatin complexes were fixed by perfusing the mice through the heart with PBS followed by 1% formalin/PBS for 10 min. Prostates or thymuses were then harvested and dissected in PBS containing 125 mM glycine to quench any further fixation. Tissue samples were then rinsed briefly in cold PBS and placed in cell lysis buffer [5 mM 1,4-piperazine diethane sulfonic acid (pH 8.0), 85 mM KCl, 0.5% Nonidet P-40] for 10 min on ice. Tissues were then homogenized using a B-dounce, and nuclei were harvested by centrifuging at 5000 rpm for 5 min at 4 C. Nuclei were then lysed in 200 ml nuclear lysis buffer [50 mM Tris-HCl (pH 8.0), 10 mM EDTA, 1% sodium dodecyl sulfate], and chromatin was sheared into 0.6- to 1.2-kb fragments. Sheared chromatin was then diluted 10-fold with dilution buffer [16.7 mM Tris-HCl (pH 8.0), 167 mM NaCl, 1.2 mM EDTA, 1.1% Triton X-100, 0.01% sodium dodecyl sulfate], yielding 2 ml of diluted chromatin per tissue sample. This volume was split so that mock rabbit IgG and specific immunoprecipitations could be performed on each individual tissue sample. Immunoprecipitations, washes, elutions, and clean-up steps were performed according to the Upstate Biotechnology ChIP protocol. Before quantitative PCR, chromatin samples were further purified over PCR purification columns (QIAGEN, Santa Clarita, CA) and eluted in 100 µl water. Quantitative PCR was performed on 2.5 µ of eluted chromatin using Sybr Green I. Quantitative PCR primers are listed in Table 2
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Animal care
All animal experiments were performed in accordance with accepted standards of humane animal care under an institutional review board-approved protocol. Castration and testosterone replacement experiments were performed as previously described.
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Results |
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5-fold) within 24 h of testosterone replacement, and FKBP5 expression remained elevated through 7 d after testosterone replacement (Fig. 1A). This expression pattern is consistent with the rapid FKBP5 induction observed in two androgen-responsive cell lines, LAPC-4 and LnCAP (Fig. 1B). Thus, androgen-responsive FKBP5 expression is conserved among mouse and human species, and it is present in both transformed and nontransformed prostate cells.
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). The orthologs were aligned using BLAST with a customized scoring matrix (Chang, L., and G. D. Stormo, manuscript submitted), and TRANSFAC 6.0 matrices were used to identify consensus AREs in conserved regions of the gene (22). This approach identified seven conserved, putative AREs (Table 1 and Fig. 2A). One site is located in the promoter at –2.5 kb, whereas the remaining sites are located in introns throughout the gene (Fig. 2A). Two perfectly conserved AREs, ARE-6 and ARE-7, are separated by only 12 bases in the fifth intron of the gene, 65.6 kb downstream of the transcription start site (Table 1 and Fig. 2A).
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). Four mouse prostates were tested individually for enrichment, relative to a mock IgG control, at each binding site after ChIP with an AR-specific antibody. Whereas the proximal promoter and AREs 1–5 failed to demonstrate reproducible enrichment by quantitative PCR, primers directed to the site of ARE-6 and -7 demonstrated enrichment ranging from 8- to 30-fold in four separate mouse prostates (Fig. 2B). Thus, AR appears to bind specifically to this downstream region of the FKBP51 gene in vivo.
Androgen regulation of the FKBP51 intron-5 enhancer element via ARE-7
ARE-6 and -7 are located within a 665-bp block of sequence that lies within intron 5 and is well conserved among mice, rats, and humans (Fig. 3). We cloned a 1-kb fragment containing the putative androgen-responsive, I5E into the Pro-36 minimal promoter-luciferase reporter vector and tested its ability to enhance reporter gene expression after androgen stimulation. In LAPC-4 cells, the I5E element enhanced reporter activity in an androgen-dependent manner (Fig. 4). Furthermore, the approximately 4-fold androgen-dependent increase in reporter activity mirrors that of the endogenous mouse FKBP51 gene after testosterone stimulation (Fig. 1B). Deletion of ARE-7, but not ARE-6, abrogated androgen-dependent I5E activity (Fig. 4). Thus, the FKBP5 I5E element responds to androgen stimulation in vitro in a manner specifically dependent on ARE-7.
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Three known AR cofactors, CBP, SRC-1, and PCAF, were tested for an interaction with the I5E element and the proximal promoter by quantitative ChIP assay (Fig. 5A). Anti-CBP ChIP assays demonstrated reproducible enrichment (5-fold) relative to mock IgG samples at the distal I5E element (n = 4). Reproducible enrichment was not observed at the proximal promoter after anti-CBP ChIP, and anti-SRC-1 and anti-PCAF ChIP assays failed to demonstrate enrichment at either the proximal promoter or distal enhancer element (Fig. 5A). Thus, CBP appears to be selectively recruited to the AR bound, distal enhancer element of the FKBP5 gene.
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In previous studies, direct looping interactions were demonstrated by the presence of proximal and distal transcription factors in a single complex as determined by ChIP assay. Thus, RNA PolII has been observed to interact both with the proximal promoter and the upstream enhancers of looped genes such as PSA and KLK2, as have AR and its cofactors (7, 26). To test for a looping interaction at the FKBP5 locus, anti-PolII quantitative ChIP assays were performed (n = 4), and PolII interactions with each putative ARE and the proximal promoter were determined (Fig. 5B). These assays indicated a strong interaction between PolII and the proximal promoter (200-fold enrichment). The remainder of the locus, including ARE-6/7 in the I5E element, demonstrated only minimal (2- to 3-fold) enrichment in the PolII ChIP (Fig. 5B). This finding, in conjunction with the fact that both AR and CBP fail to interact with the proximal promoter (Figs. 2B and 5A), appears to rule out a single looping complex as the mechanism of gene regulation by the I5E enhancer.
An alternative regulatory mechanism for transactivation could involve global chromatin remodeling at the FKBP5 locus after AR binding and cofactor recruitment. Such a mechanism has been previously demonstrated in Rat-1 fibroblasts, in which binding of the RE-1 silencing transcription factor/neuron-restrictive silencing factor transcription factor to a discrete enhancer, followed by subsequent cofactor recruitment, leads to chromatin remodeling and silencing of a large genomic region that encompasses the entire NaCh II gene (27).
To test the global remodeling hypothesis, histone H3 acetylation was assayed in the prostates of castrated or uncastrated mice by quantitative ChIP (n = 4 and 7, respectively). These experiments revealed a dynamic pattern of histone acetylation at the FKBP5 locus (Fig. 5C). Hyperacetylation was observed at the proximal promoter and at AREs located near the proximal promoter, regardless of castration status. Genomic regions between the highly acetylated proximal promoter and the I5E demonstrated considerably lower levels of histone acetylation, and these regions also exhibited no difference between castrated and uncastrated prostates. In contrast, a statistically significant difference in acetylation was observed between the prostates of castrated and uncastrated mice at ARE-6/7 in the I5E (8-fold difference, P < 0.05). This finding is consistent with the earlier observations of AR binding and CBP recruitment. However, the effects of AR complex formation on chromatin structure appear to be confined to the distal I5E element, thereby excluding global chromatin remodeling as a mechanism for FKBP5 transactivation. Altogether, these findings implicate a potentially novel but currently ill-defined mechanism of communication between the distal enhancer and proximal promoter complexes.
Regulation of the I5E element by other steroid hormones
Previous studies have shown that glucocorticoids and progestins also enhance expression of the FKBP5 gene (14, 15, 16, 20). Given the fact that AR, GR, and PR all share a common consensus binding site, we postulated that the I5E functions as a common mediator of androgen, glucocorticoid, and progestin signals. This hypothesis was tested by transfecting LAPC-4 cells with the I5E-luciferase reporter construct, with or without cotransfected GR or PR. Cells were then stimulated with dexamethasone or progesterone. Cells that were not cotransfected with GR or PR failed to demonstrate enhanced I5E activity in response to hormone stimulation (Fig. 6). However, cotransfection of either GR or PR resulted in a 12- or 8-fold increase in enhancer activity after dexamethasone or progesterone stimulation, respectively (Fig. 6). Thus, GR and PR can regulate FKBP5 gene expression in vitro.
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To test this hypothesis, wild-type BL6 mice were injected ip with vehicle or 200 µg of dexamethasone phosphate (Dex-Phos) (n = 5 for each treatment) (28). Thymuses were harvested 24 h after treatment. Dex-Phos-treated mice exhibited qualitatively smaller thymuses than those of vehicle-treated mice. This finding was consistent with previous observations of glucocorticoid effects on thymocytes, and it demonstrates native GR activity in these cells (28). At harvest, each thymus sample was divided such that mRNA could be obtained and matched with ChIP assays performed with anti-GR, anti-CBP, anti-SRC-1, anti-PCAF, and anti-histone H3. Surprisingly, neither vehicle nor Dex-Phos-treated mice demonstrated reproducible GR binding at any site in the FKBP5 gene, although a 23-fold enrichment was observed at ARE-6/7 in a single thymus (Fig. 7A). Dex-Phos treatment did not alter FKBP5 expression, nor did it result in CBP, SRC-1, or PCAF binding (Fig 7B and data not shown). Histone acetylation was unaffected by Dex-Phos treatment (data not shown).
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Discussion |
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). Nevertheless, in vivo ChIP assays revealed that only ARE-7 binds to AR in the mouse prostate. Thus, the simple identification of a conserved, high-affinity AR binding site in an androgen target gene does not necessarily imply in vivo function. The mechanism through which the AR complex at the I5E element communicates with the proximal promoter remains an outstanding question for ongoing study. Exhaustive work on model systems of development, including sea urchins, Drosophila, stickleback fish, mice, and chickens, has led to an increased awareness of the role that distal enhancers play in regulating complexes spatial and temporal patterns of gene expression in vivo (29, 30, 31, 32, 33, 34). At times, functional enhancers can be located hundreds of kilobases away from the basal transcription apparatus. How then might these distant genomic regions communicate?
Most studies of distant enhancer function have concentrated on the locus control region (LCR) of the ß-globin gene, and from these studies, several concepts have emerged that bear relevance to FKBP5 regulation in the prostate (35, 36, 37, 38). The LCR consists of five DNase I-hypersensitive sites that span 20 kb and are located 40–60 kb upstream of the ß-globin locus (37). Current evidence indicates that in the erythroid lineage, in which ß-globin is expressed, the LCR and ß-globin promoter maintain a close proximity to each other (36, 37, 38). This relationship occurs under the auspices of a complex termed the active chromatin hub (ACH), the precise components of which are still emerging (39). However, before integration into the ACH, transcription factor complexes assemble at the proximal promoter and distal LCR independently of one another (38). In remarkable similarity to the I5E, transcription factors that directly contact DNA in the LCR (e.g. GATA-1) are not enriched at the proximal promoter, despite clear evidence placing the ß-globin promoter and the LCR near each other during active transcription (36). This finding suggests an indirect interaction between transcription factors that bind distant enhancers and their respective proximal promoters.
It is worthwhile to note the differences between the architectures of the PSA and ß-globin genes. The contribution of the PSA enhancer to active transcription can be discerned relatively easily. A single complex consisting of AR and its cofactors assembles to create a direct link between the enhancer and promoter elements. This complex possesses HAT activity that acetylates histones at the proximal promoter, leading to subsequent enhancement of PolII activity (7). Distal promoter-enhancer interactions appear to be more complex at the ß-globin locus because proximal and distal complexes assemble independently and because the components of the ACH are still coming to light (35, 37, 38, 39). FKBP5 regulation appears to follow the ß-globin model more closely than the PSA model. AR, bound to an enhancer located 65 kb downstream of the initiation site, does not interact directly with the proximal promoter, nor does its cofactor CBP. Histones at the proximal promoter are highly acetylated, regardless of AR function, and chromatin remodeling in the presence of androgen is confined to the distal enhancer. Finally, PolII does not directly communicate with the downstream enhancer, save for the 2- to 3-fold enrichment that occurs throughout the locus and likely represents processivity. Given these findings, it will be interesting to use previously described techniques such as RNA tagged recovery of associated proteins and chromosome confirmation capture to determine whether an indirect looping interaction mediates I5E activity (36, 38). Clarifying this interaction will further illuminate AR function in vivo that will, in turn, broaden our understanding of prostate physiology and prostate cancer.
In addition to characterizing the mechanisms of AR-mediated FKBP5 expression in the prostate, we have explored the possibility that other nuclear hormone receptors might mediate FKBP5 expression in nonprostatic tissues via the I5E. The I5E can respond to glucocorticoid and progestin stimulation in vitro. FKBP5 is expressed in nonprostatic tissues, including the thymus and umbilical cord, which integrate steroid hormone signals as a means of maintaining homeostasis. Thymocytes express GR and respond physiologically to glucocorticoid stimulation. Surprisingly, however, we have found that dexamethasone does not alter FKBP5 expression in the thymus (Fig. 7). Furthermore, FKBP5 histone acetylation is not altered in response to dexamethasone stimulation, and GR and its cofactors do not bind the FKBP5 locus in the thymuses of dexamethasone-treated or untreated mice (Fig. 7 and data not shown). Thus, in vivo support for a GR or PR association with the I5E remains to be established, and these interactions should not be presumed simply on the basis of in vitro precedent.
The importance of confirming in vitro hypotheses in an in vivo setting is underscored by other recent investigations of FKBP5 hormone response elements as well. In A549 lung and T47-D breast carcinoma cells, Hubler and Scammell (40) localized GR- and PR-mediated FKBP5 regulation to ARE-5 and ARE-7. In stark contrast to our data, however, these authors found that androgens did not transactivate an ARE-6/7-containing element in androgen-responsive LnCAP cells. These contradictory findings highlight the difficulties encountered when using in vitro reporter assays as a proxy for in vivo interactions. Whereas different reporter constructs in different prostate cell lines have yielded differing assessments of AR function, in vivo ChIP assays clearly and reproducibly demonstrate an interaction between AR and the I5E element in the mouse prostate, and they fail to indicate an interaction between GR and the I5E in the thymus. In light of these contradictions, the possibility of artifactual findings must be considered when interpreting in vitro data.
Given the complexity of mammalian gene regulation, it is imperative that efforts to decipher the mammalian cis-regulatory code, for androgen-responsive genes or otherwise, regard in vivo data as a gold standard for bona fide cis-trans interactions. The methodology used in this paper facilitates this goal because ChIP assays may be performed on tissues derived from several mice (n = 4–7 mice in this work), and these samples may be individually screened for enrichment at dozens of putative transcription factor binding sites. In this fashion, we expect that additional direct interactions between AR and androgen-responsive genes will be elucidated in the near future and that these interactions will illuminate the mechanisms through which androgens regulate the growth and survival of prostate epithelia.
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Acknowledgments |
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Footnotes |
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First Published Online October 6, 2005
Abbreviations: ACH, Active chromatin hub; AR, androgen receptor; ARE, androgen-responsive element; CBP, cAMP response element-binding protein; ChIP, chromatin immunoprecipitation; Dex-Phos, dexamethasone phosphate; EtOH, ethyl alcohol; GR, glucocorticoid receptor; HAT, histone acetyl-transferase; I5E, intron-5 enhancer; KLK2, kallikrein-2; LCR, locus control region; PCAF, p300/CBP-associated factor; PolII, polymerase II; PR, progesterone receptor; PSA, prostate-specific antigen; qRT-PCR, quantitative RT-PCR; SRC, steroid receptor coactivator.
Received August 5, 2005.
Accepted for publication September 16, 2005.
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