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Glucocorticoid Receptor Domain Requirements for Chromatin Remodeling and Transcriptional Activation of the Mouse Mammary Tumor Virus Promoter in Different Nucleoprotein Contexts*

Open AccessPublished:May 23, 2002DOI:https://doi.org/10.1074/jbc.M203898200
      The glucocorticoid receptor (GR) contains several activation domains, τ1 (AF-1), τ2, and AF-2, which were initially defined using transiently transfected reporter constructs. Using domain mutations in the context of full-length GR, this study defines those domains required for activation of the mouse mammary tumor virus (MMTV) promoter in two distinct nucleoprotein configurations. A transiently transfected MMTV template with a disorganized, accessible chromatin structure was largely dependent on the AF-2 domain for activation. In contrast, activation of an MMTV template in organized, replicated chromatin requires both domains but has a relatively larger dependence on the τ1 domain. Domain requirements for GR-induced chromatin remodeling of the latter template were also investigated. Mutation of the AF-2 helix 12 domain partially inhibits the induction of nuclease hypersensitivity, but the inhibition was relieved in the absence of τ1, suggesting the occurrence of an important interaction between the two domains. Further mutational analysis indicates that GR-induced chromatin remodeling requires the ligand-binding domain in the region of helix 3. Our study shows that the GR activation surfaces required for transcriptional modulation of a target promoter were determined in part by its chromatin structure. Within a particular cellular environment the GR appears to possess a significant degree of versatility in the mechanism by which it activates a target promoter.
      GR
      glucocorticoid receptor
      LBD
      ligand-binding domain
      DBD
      DNA-binding domain
      MMTV
      mouse mammary tumor virus
      HA
      hemagglutinin
      AF-2
      activation function 2
      CBP
      CREB-binding protein
      Nuclear receptors have provided fruitful models for studying the mechanisms by which transcription factors work (reviewed in Ref.
      • Aranda A.
      • Pascual A.
      ). The steroid receptors are a ligand-inducible class of this family and the glucocorticoid receptor (GR)1 cDNA was the first of these to be cloned and sequenced (
      • Hollenberg S.M.
      • Weinberger C.
      • Ong E.S.
      • Cerelli G.
      • Oro A.
      • Lebo R.
      • Thompson E.B.
      • Rosenfeld M.G.
      • Evans R.M.
      ). The GR has a ubiquitous expression pattern in mammals and is involved in regulation of a number of biological processes through regulation of various target genes. In the mammary gland, it is essential for the differentiation process that leads to lactation.
      The mechanism of GR transactivation has been the focus of a large number of studies, and domains of the GR involved in transcriptional activation have been defined. One of these domains, τ1 or AF-1, is located in the amino-terminal region of the receptor (
      • Godowski P.J.
      • Rusconi S.
      • Miesfeld R.
      • Yamamoto K.R.
      ,
      • Gigüere V.
      • Hollenberg S.M.
      • Rosenfeld M.G.
      • Evans R.M.
      ,
      • Hollenberg S.M.
      • Evans R.M.
      ). Its core region is unstructured in solution but can form an α-helical structure in a hydrophobic environment (
      • Dahlman-Wright K.
      • Baumann H.
      • McEwan I.J.
      • Almlof T.
      • Wright A.P.
      • Gustafsson J.A.
      • Hard T.
      ,
      • Dahlman-Wright K.
      • McEwan I.J.
      ). Helix-breaking proline substitutions (
      • Dahlman-Wright K.
      • McEwan I.J.
      ) or mutations in hydrophobic amino acid residues decrease its transactivation potential (
      • Almlof T.
      • Gustafsson J.A.
      • Wright A.P.
      ,
      • Almlof T.
      • Wallberg A.E.
      • Gustafsson J.A.
      • Wright A.P.
      ). The τ1 domain is also important in mediating transcriptional repression by the GR (
      • Iniguez-Lluhi J.A.
      • Lou D.Y.
      • Yamamoto K.R.
      ). It has been shown to interact with a number of factors and complexes including TBP (
      • Ford J.
      • McEwan I.J.
      • Wright A.P.
      • Gustafsson J.A.
      ), TFIID (
      • Ford J.
      • McEwan I.J.
      • Wright A.P.
      • Gustafsson J.A.
      ,
      • McEwan I.J.
      • Wright A.P.H.
      • Dahlman-Wright K.
      • Carlstedt-Duke J.
      • Gustafsson J.-Å.
      ), CBP (
      • Almlof T.
      • Wallberg A.E.
      • Gustafsson J.A.
      • Wright A.P.
      ), members of the DRIP/vitamin D receptor-interacting proteins complex (
      • Hittelman A.B.
      • Burakov D.
      • Iniguez-Lluhi J.A.
      • Freedman L.P.
      • Garabedian M.J.
      ), the yeast histone acetyltransferase complex SAGA (
      • Wallberg A.E.
      • Neely K.E.
      • Gustafsson J.A.
      • Workman J.L.
      • Wright A.P.
      • Grant P.A.
      ), and the ATP-dependent chromatin remodeling complex, SWI/SNF (
      • Wallberg A.E.
      • Neely K.E.
      • Hassan A.H.
      • Gustafsson J.A.
      • Workman J.L.
      • Wright A.P.
      ).
      Two other GR transactivation domains are located in the ligand-binding region. The first, τ2, is a small region at the amino-terminal end of the ligand-binding domain (LBD) (
      • Hollenberg S.M.
      • Evans R.M.
      ). It contains sequences that are conserved among the steroid receptors and has been shown to mediate transactivation when fused to a DNA-binding domain (DBD) (
      • Hollenberg S.M.
      • Evans R.M.
      ,
      • Milhon J.
      • Lee S.
      • Kohli K.
      • Chen D.
      • Hong H.
      • Stallcup M.R.
      ). It also harbors a nuclear matrix targeting signal and interacts with Hic-5, a protein that associates with the nuclear matrix and also potentiates GR action (
      • Yang L.
      • Guerrero J.
      • Hong H.
      • DeFranco D.B.
      • Stallcup M.R.
      ,
      • Tang Y.
      • Getzenberg R.H.
      • Vietmeier B.N.
      • Stallcup M.R.
      • Eggert M.
      • Renkawitz R.
      • DeFranco D.B.
      ). The other known transactivation domain of the GR, termed AF-2, is a larger region within the COOH terminus of the LBD. In other nuclear receptors it is thought to comprise a surface formed by α-helices 3, 5, 6, and 12 (19, 20). Helix 12, termed the AF-2 AD core, undergoes a conformational change upon binding of ligand that generates a surface for interaction with either corepressors or coactivator proteins, dependent on whether the ligand is an agonist or antagonist (reviewed in Ref.
      • Aranda A.
      • Pascual A.
      ). Coactivators include SRC1, TIF2/GRIP1, CBP/p300, and P/CAF, some of which are histone acetyltransferases (reviewed in Ref.
      • Torchia J.
      ).
      Consistent with the fact that it interacts with histone acetyltransferases and ATP-dependent remodeling complexes, the GR is known to induce modification of chromatin structure. A number of target genes have glucocorticoid-inducible nuclease hypersensitive sites (
      • Becker P.
      • Renkawitz R.
      • Schutz G.
      ,
      • Zaret K.S.
      • Yamamoto K.R.
      ,
      • Richard-Foy H.
      • Hager G.L.
      ). Perhaps the best studied of these is the mouse mammary tumor virus (MMTV) promoter. The GR has been shown to activate this promoter by two distinct mechanisms, depending on its chromatin structure (
      • Archer T.K.
      • Lefebvre P.
      • Wolford R.G.
      • Hager G.L.
      ). When the promoter is organized into replicating chromatin, either as an episome or integrated into the genome, the GR induces a chromatin remodeling event in the nucleosome regions containing its binding sites (
      • Richard-Foy H.
      • Hager G.L.
      ,
      • Fragoso G.
      • Pennie W.D.
      • John S.
      • Hager G.L.
      ). This is mechanistically necessary for transcriptional activation because it allows access of previously excluded transcription factors NF1 and Oct1 (
      • Archer T.K.
      • Lefebvre P.
      • Wolford R.G.
      • Hager G.L.
      ,
      • Cordingley M.G.
      • Riegel A.T.
      • Hager G.L.
      ,
      • Lee H.-L.
      • Archer T.K.
      ). The GR also facilitates the association of the basal transcription machinery with the promoter, which presumably activates transcription (
      • Lee H.-L.
      • Archer T.K.
      ). Therefore, this form of the MMTV promoter is derepressed and then activated through GR action.
      When the MMTV promoter is introduced into cells as a transiently transfected reporter construct, it adopts a disorganized and accessible chromatin structure to which NF1 and Oct1 bind constitutively rather than in a hormone-dependent fashion (
      • Archer T.K.
      • Lefebvre P.
      • Wolford R.G.
      • Hager G.L.
      ,
      • Lee H.-L.
      • Archer T.K.
      ). This template does not undergo remodeling but is activated by GR, probably through increased association of the basal machinery. Once the MMTV template in organized chromatin is remodeled and derepressed, it is unclear whether GR activates it by the same mechanism employed at the transiently transfected MMTV template. One way to approach this question would be to assess the effect of various GR activation domain mutants on the ability of the two templates to be activated. These domains were defined using transiently transfected reporter constructs. It is not known whether these same domains would be necessary for activation of a promoter in repressed chromatin.
      There is conflicting information on the domains required for chromatin remodeling induced by the GR. Several studies indicate that the SWI/SNF family of ATP-dependent remodeling complexes are involved in transactivation by GR in mammalian cells (
      • Wallberg A.E.
      • Neely K.E.
      • Hassan A.H.
      • Gustafsson J.A.
      • Workman J.L.
      • Wright A.P.
      ,
      • Muchardt C.
      • Yaniv M.
      ,
      • Nie Z.
      • Xue Y.
      • Yang D.
      • Zhou S.
      • Deroo B.J.
      • Archer T.K.
      • Wang W.
      ). Both in vivo (
      • Fryer C.J.
      • Archer T.K.
      ) and in vitro (
      • Ostlund Farrants A.K.
      • Blomquist P.
      • Kwon H.
      • Wrange O.
      ,
      • Fletcher T.M.
      • Xiao N.
      • Mautino G.
      • Baumann C.T.
      • Wolford R.
      • Warren B.S.
      • Hager G.L.
      ) studies suggest a role for the SWI/SNF complex in the induction of nuclease hypersensitivity by GR at the MMTV promoter. GR has also been shown to interact physically with the SWI/SNF complex (
      • Wallberg A.E.
      • Neely K.E.
      • Hassan A.H.
      • Gustafsson J.A.
      • Workman J.L.
      • Wright A.P.
      ,
      • Nie Z.
      • Xue Y.
      • Yang D.
      • Zhou S.
      • Deroo B.J.
      • Archer T.K.
      • Wang W.
      ,
      • Fryer C.J.
      • Archer T.K.
      ,
      • Yoshinaga S.K.
      • Peterson C.L.
      • Herskowitz I.
      • Yamamoto K.R.
      ). Recently, Wallberg et al. (
      • Wallberg A.E.
      • Neely K.E.
      • Hassan A.H.
      • Gustafsson J.A.
      • Workman J.L.
      • Wright A.P.
      ) showed that activation by GR in yeast was dependent on the presence of Snf6, a member of the ATP-dependent nucleosome remodeling complex, SWI/SNF. This dependence was mediated through the τ1 domain, which was shown to interact directly with the yeast SWI/SNF complex in vitroand, when fused to a heterologous DNA-binding domain, activate transcription on in vitro assembled chromatin in a SWI/SNF-dependent manner. However, Muchardt and Yaniv (
      • Muchardt C.
      • Yaniv M.
      ) showed that expression of the SWI/SNF ATPase, brahma, greatly potentiated GR-mediated promoter activation in a manner dependent on the GR DBD. Further complexity emerged from the studies of DiRenzo et al. (
      • DiRenzo J.
      • Shang Y.
      • Phelan M.
      • Sif S.
      • Myers M.
      • Kingston R.
      • Brown M.
      ) who showed that the estrogen receptor interacts functionally and physically with this complex in an AF-2-dependent fashion. Thus, multiple receptor domains have been implicated in interactions with the SWI/SNF complex but none of these studies assayed chromatin remodeling directly.
      In this study we examine the role of each of the activation domains in GR function in vivo. We have taken advantage of a GR mutant, C656G, which binds its ligand with higher affinity than wild type GR (
      • Chakraborti P.K.
      • Garabedian M.J.
      • Yamamoto K.R.
      • Simons S.S., Jr.
      ). We showed previously that this receptor is capable of remodeling chromatin and activating transcription from an MMTV promoter in ordered chromatin (
      • Smith C.L.
      • Htun H.
      • Wolford R.G.
      • Hager G.L.
      ). In the context of the full-length C656G receptor, mutations were introduced into the previously defined activation domains. These mutations were assayed for their role in transcriptional activation of the transiently transfected and stably replicating MMTV templates as well as in GR-dependent chromatin remodeling at the latter. The results show that the GR uses its domains differently in the transactivation of the MMTV promoter in distinct nucleoprotein environments. In addition, through direct measurement of chromatin remodeling we have determined that the ligand-binding domain plays a critical role in mediating this process. Our findings strongly support the idea that the mechanism by which the GR modulates transcription is not only dependent on the nature of the target promoter but also on its chromatin configuration.

      DISCUSSION

      Our study into the mechanism by which the GR activates the same promoter in different nucleoprotein contexts shows that the GR was a highly versatile protein that utilizes distinct domains and activation mechanisms to regulate transcription. A previous study reported that distinct domains are required for GR activation in different cellular contexts (
      • Bocquel M.T.
      • Kumar V.
      • Stricker C.
      • Chambon P.
      • Gronemeyer H.
      ); whereas τ1 was highly active in CV1 cells, it had much less transactivation capacity in HeLa cells where the LBD was much more active. They speculated that these differing domain dependences reflected varying cellular concentrations of cofactors. However, our study shows that this was true even within a particular cellular environment and was dependent on nucleoprotein context of a specific target promoter. In addition, we have defined a region of the GR important for productive interaction with machinery that catalyzes chromatin remodeling in mammalian cells and have provided evidence for a functionally important cross-talk between the AF-2 and τ1 domains. The results of our study have implications for understanding the tissue-specific regulation of target genes by steroid receptors, which may be determined by the availability of various cofactors as well as the chromatin structure of the target promoter.
      The GR domains required for various steps in activation of the two structurally distinct MMTV templates are summarized in Fig.9. Activation of a transiently transfected MMTV promoter construct by the GR was largely dependent on the GR LBD in our cell lines. Mutation of amino acids in helices 3 or 12 significantly reduced activation. However, a mutation in the τ2 region had no effect, which differs from the results of Milhon et al. (
      • Milhon J.
      • Lee S.
      • Kohli K.
      • Chen D.
      • Hong H.
      • Stallcup M.R.
      ). The disparity may lie in the species of receptor used (rat versus mouse) or the cell type assayed (mammaryversus kidney origin). In contrast to the LBD mutations, deletion or mutation of τ1 impaired activation of the transient template by only 20–30%. The importance of the τ1 region for activation of transiently transfected promoters has been found to vary depending on the cell line used (
      • Hollenberg S.M.
      • Evans R.M.
      ,
      • Iniguez-Lluhi J.A.
      • Lou D.Y.
      • Yamamoto K.R.
      ,
      • Bocquel M.T.
      • Kumar V.
      • Stricker C.
      • Chambon P.
      • Gronemeyer H.
      ,
      • Danielsen M.
      • Northrop J.P.
      • Jonklaas J.
      • Ringold G.M.
      ).
      Figure thumbnail gr9
      Figure 9A summary of GR domain requirements for various steps in the activation mechanisms of the two structurally distinct MMTV templates. Dex, dexamethasone.
      Activation of the stably replicating MMTV promoter required both the τ1 domain and amino acid residues in helices 3 and 12 of the AF-2 domain. Interestingly, the hydrophobic residues in τ1 required for full activation of the transient template made only a small contribution to activation of the stable MMTV template. Thus the region of τ1 necessary for activation in the context of ordered chromatin does not completely coincide with that required for activation of transient templates and interaction with the DRIP complex (
      • Hittelman A.B.
      • Burakov D.
      • Iniguez-Lluhi J.A.
      • Freedman L.P.
      • Garabedian M.J.
      ). This result strongly suggests that τ1 interacts with different sets or domains of transcriptional cofactors at the two MMTV templates.
      The τ1 domain was not required for chromatin remodeling, which indicates that its main contribution to transactivation at the stable template was downstream of template derepression and NF1 binding, and may be mediated through interactions with the basal transcription machinery. Consistent with this idea is the fact that the τ1 domain has been shown to interact with TBP and the TFIID complex (
      • Ford J.
      • McEwan I.J.
      • Wright A.P.
      • Gustafsson J.A.
      ,
      • McEwan I.J.
      • Wright A.P.H.
      • Dahlman-Wright K.
      • Carlstedt-Duke J.
      • Gustafsson J.-Å.
      ) as well as CBP (
      • Almlof T.
      • Wallberg A.E.
      • Gustafsson J.A.
      • Wright A.P.
      ). The AF-2 helix 12 domain also functions downstream of template derepression. This was evidenced by the fact that the Δτ1/AF2dm12 receptor is a less efficient activator than the Δτ1 receptor even though it can fully remodel chromatin at the stable MMTV template. The helix 12 domain may thus participate in a common activation step at both MMTV templates.
      Our study clearly shows that the GR LBD plays an important role in the induction of chromatin remodeling at the stable MMTV template. This is consistent with our previous work showing that a different LBD mutant of GR failed to induce remodeling (
      • Sheldon L.A.
      • Smith C.L.
      • Bodwell J.E.
      • Munck A.U.
      • Hager G.L.
      ). Mutation of helix 12 residues causes a significant impairment of the ability of the GR to induce chromatin remodeling and subsequent NF1 binding, but only in the presence of the τ1 domain. This observation suggests that helix 12 is not directly necessary for productive interaction with remodeling machinery but may facilitate this process through cross-talk with τ1. A mutation in LBD helix 3 either alone or in the context of the Δτ1/AF2dm12 receptor significantly impaired chromatin remodeling, suggesting that this region of the LBD plays a role distinct from that of helix 12. However, remodeling was never completely abolished. The helix 3 region may provide part of an interaction surface for the remodeling complex and/or facilitate its interaction with another domain. Previous studies indicated that the DBD of the GR may be important for interaction and function of SWI/SNF complexes (
      • Muchardt C.
      • Yaniv M.
      ,
      • Yoshinaga S.K.
      • Peterson C.L.
      • Herskowitz I.
      • Yamamoto K.R.
      ). In addition, a recent report showed that the SWI/SNF complex makes physical and functional interactions with transcription factors, which like the GR, contain zinc finger DBDs (
      • Kadam S.
      • McAlpine G.S.
      • Phelan M.L.
      • Kingston R.E.
      • Jones K.A.
      • Emerson B.M.
      ). The proximity of helix 3 to the GR DBD leaves open the possibility that both of these domains may serve to recruit or interact with the remodeling machinery.
      A recent report showed that τ1 interacted physically and functionally with purified yeast SWI/SNF complex (
      • Wallberg A.E.
      • Neely K.E.
      • Hassan A.H.
      • Gustafsson J.A.
      • Workman J.L.
      • Wright A.P.
      ). Our results showing that τ1 was dispensable for chromatin remodeling at the MMTV promoter in organized chromatin may differ based on subunit differences between yeast and mammalian SWI/SNF complexes and their interactions with other basic transcription complexes (
      • Sudarsanam P.
      • Winston F.
      ). The promoter context may also influence the function of various GR domains. In addition, it is possible that a complex other than SWI/SNF can remodel MMTV chromatin in mammalian cells (
      • Di Croce L.
      • Koop R.
      • Venditti P.
      • Westphal H.M.
      • Nightingale K.P.
      • Corona D.F.
      • Becker P.B.
      • Beato M.
      ). Our results are more in line with those of DiRenzo et al. (
      • DiRenzo J.
      • Shang Y.
      • Phelan M.
      • Sif S.
      • Myers M.
      • Kingston R.
      • Brown M.
      ), who showed a physical and functional interaction of human SWI/SNF complex with the LBD of estrogen receptor. However, their transactivation assays were carried out on transiently transfected reporters that may not undergo the type of remodeling observed at the MMTV promoter in organized chromatin. Our study is the only report to date that directly assays effects of various receptor domains on the induction of nuclease hypersensitivity at a target promoter in mammalian cells.
      Our results have also provided evidence for a functionally important cross-talk between the τ1 and AF-2 domains. First, the presence of the τ1 domain has a deleterious effect on dose response of the GR containing mutations in helices 3 and/or 12 (AF2dm12 and AF2dm12/K597A) because when it is removed (Δτ1/AF2dm12 and Δτ1/AF2dm12/K597A) the EC50 improves to a value close to that of the C656G receptor (see Table I). This same effect was observed in chromatin remodeling assays as described above (AF2dm12 versusΔτ1/AF2dm12, Fig. 6). Although there is no evidence for a direct interaction between τ1 and the GR LBD, some steroid receptor coactivators are capable of interacting with both domains (
      • Hittelman A.B.
      • Burakov D.
      • Iniguez-Lluhi J.A.
      • Freedman L.P.
      • Garabedian M.J.
      ,
      • McInerney E.M.
      • Tsai M.J.
      • O'Malley B.W.
      • Katzenellenbogen B.S.
      ,
      • Onate S.A.
      • Boonyaratanakornkit V.
      • Spencer T.E.
      • Tsai S.Y.
      • Tsai M.J.
      • Edwards D.P.
      • O'Malley B.W.
      ). It is possible that coincident interaction of the two activation domains with each other and/or bridging proteins may cause a conformational change in the receptor that facilitates stable binding of ligand and allows another region of the GR to make contact with the remodeling machinery.
      Why are different GR domains required for activation of the same promoter in distinct nucleoprotein contexts? It has been established that the nucleoprotein structure of the MMTV promoter influences its mechanism of activation by the GR (
      • Archer T.K.
      • Lefebvre P.
      • Wolford R.G.
      • Hager G.L.
      ). Incorporation of the promoter into organized chromatin necessitates remodeling and derepression prior to activation of transcription. A distinct set of factors is likely to be recruited to the MMTV promoter in organized chromatin to participate in remodeling and the subsequent transcriptional activation and elongation in the context of positioned nucleosomes and linker histones (
      • Bresnick E.H.
      • Bustin M.
      • Marsaud V.
      • Richard-Foy H.
      • Hager G.L.
      ). This greater complexity may be reflected by the fact that both transcriptional domains of the GR (τ1 and the LBD) are required for activation of the stable template, whereas activation of the transient template is largely dependent only on the LBD. Another interesting possibility is that the interaction of GR with nucleosomes may serve as an allosteric effector, much like its interaction with various GREs (
      • Lefstin J.A.
      • Thomas J.R.
      • Yamamoto K.R.
      ,
      • Starr D.B.
      • Matsui W.
      • Thomas J.R.
      • Yamamoto K.R.
      ). At a nucleosome the GR may present various domains necessary for activation in that context.

      Acknowledgments

      We thank Dr. S. Stoney Simons (National Institutes of Health) for generously providing an expression construct for the C656G receptor. We are also grateful to members of the Smith and Hager laboratories for helpful discussions.

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