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Department of Anatomy, University of Wisconsin Medical School, Madison, Wisconsin,1 Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey2
Received 30 March 2004/ Returned for modification 10 June 2004/ Accepted 31 August 2004
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ABSTRACT |
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INTRODUCTION |
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-myosin heavy chain (MHC) expression is synergistically activated by myocyte-specific enhancer factor 2 (MEF2) and the thyroid hormone receptor. This activation depends on the binding of each factor to the DNA target sequences (25). The ventricular chamber-specific homeobox protein Irx4 is essential for activation and repression of the cardiac ventricular and atrial MHC expression, respectively (2). The cardiac -actin expression is activated by serum response factor (SRF), which recruits the murine cardiac-restricted homeobox protein, Nkx2.5 (4) or myocardin (44) for synergistic activation. The GATA4 transcription factor transactivates the cardiac muscle-specific troponin C promoter in nonmuscle cells (18).
Recent evidence suggests that transcriptional repressors play important roles in regulating cardiac muscle gene expression. MEF2, whose activity is essential for early normal cardiac development and muscle differentiation (28), is inhibited by Twist, a basic helix-loop-helix protein that is specifically expressed in the mesoderm (38). Activated Notch (45) and histone deacetylase, a general transcriptional repressor (30, 49), have been shown to directly interact with MEF2 to inhibit the MEF2 transcriptional activities. The thyroid hormone receptor plays a critical role in activating cardiac -MHC (20, 25). The transcriptional activity of the thyroid hormone receptor can be repressed by interacting with a nuclear receptor corepressor, SMART/NcoR, which results in silencing or repressing the target gene activation (8, 35). An unusual homeodomain protein, HOP, inhibits the activation of atrial natriuretic factor (ANF), cardiac -actin, and SM22 (37) by interacting with SRF to inhibit SRF-dependent activation. A GATA4-interacting factor, Friend of GATA-2 (FOG-2), represses GATA4-mediated transcriptional activation of several cardiac gene promoters, including the ANF, BNP, and cardiac muscle-specific troponin C (40, 42).
The molecular mechanism of the regulation of ANF expression has been studied extensively because of its early onset of expression and its cardiac-specific pattern of expression in development. Near the time of birth, the expression of ANF in the ventricle of the normal heart decreases significantly. However, the ANF gene is reexpressed in response to hypertrophic stimulation (7, 34). Expression of the ANF gene is activated by either Nkx2.5 or GATA4 or both with synergism (9, 26). The T box-containing transcription factor Tbx5 associates with Nkx2.5 and synergistically activates ANF expression in vitro (3, 17). The ANF promoter is also a target of PITX2 homeobox protein and one of the PITX2 isoforms, PITX2C, can synergistically activate the ANF promoter with Nkx2.5 (12).
Jumonji (JMJ) is a member of the jumonji family of transcription factors (for reviews, see references 1 and 6). JMJ is a nuclear factor (27) that contains a domain homologous to a DNA-binding domain of the A/T-rich interaction domain (ARID) transcription factors based on amino acid sequence analysis (13, 16, 19, 24). We and others have previously demonstrated that the jmj gene plays a critical role in the development of the heart (27) and other organs (23, 33, 41). Cardiac defects in jmj mutant mice embryos include ventricular septal defects, double outlet right ventricles, and thin ventricular walls (27). Examination of the jmj homozygote mutants revealed that regulation of cardiac-specific gene expression was defective in the hearts (27). It was of interest that down-regulation of the ANF gene expression, which occurs in the normal ventricle near birth, was defective in the hearts of the mutants compared to those of the wild-type littermates (27). These data suggest that JMJ suppresses expression of the ANF gene as the heart develops to maturity. The recent report regarding the structural and functional analyses of JMJ showed that JMJ contains domains for the powerful transcriptional repression, DNA binding, and nuclear localization signal (22). Together, these data led us to investigate the molecular mechanism of JMJ on regulating ANF gene expression.
The present study demonstrates that JMJ inhibited ANF activation by Nkx2.5 and GATA4. JMJ interacts physically with cardiac-restricted transcription factors Nkx2.5 and GATA4 and represses their abilities to activate target gene expression. Although we identified two JMJ-binding sites in the ANF enhancer, these JMJ-binding sites were dispensable in ANF repression by JMJ. This study provides molecular mechanisms of cardiac-specific gene regulation and, therefore, of cardiac development, through the repression function of JMJ in ANF gene expression.
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MATERIALS AND METHODS |
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Transfection and reporter gene assay. Neonatal primary rat cardiomyocytes were prepared and transfected by Lipofectamine (Invitrogen) as described elsewhere (32). Transient transfection assays were done by the calcium phosphate precipitation method as described previously (22, 26). Briefly, mouse embryo fibroblast (10T1/2) cells in 60-mm dish plates were transfected with 1 to 2 µg of reporter gene and/or various transcription factors (Nkx2.5, GATA4, and/or JMJ) in mammalian expression vectors and 0.5 µg of pCMV-ßgal. Two days after glycerol shock, cell lysates were assayed (Promega) for luciferase activity by using a luminometer according to the manufacturer's recommendations. Reporter gene activity was normalized to ß-galactosidase activity to correct for variations in transfection efficiency. Data are given as means ± standard errors. Statistical analyses were performed by using the analysis of variance. The posttest comparison was performed by paired t test. Results were accepted as significant when P was <0.05.
To examine whether cotransfection of JMJ affects the expression levels of Nkx2.5 or GATA4, Western blot analysis was performed as described previously (22).
Protein-protein interaction. To examine the in vivo association of JMJ with Nkx2.5 or GATA4, coimmunoprecipitation was performed as described previously (26) with minor modifications. Briefly, human embryonic kidney 293 cells (3 x 106 cells/10-cm culture dish) were transfected with 6 µg of JMJ/pFLAG-CMV2 and/or 3 µg of Nkx2.5/pcDNA3.1-myc or 3 µg of GATA4/pcDNA3.1-myc by using Lipofectamine and Plus reagents (Invitrogen). The cells were briefly sonicated in 1.5 ml of a lysis buffer (50 mM HEPES [pH 7.4], 150 mM NaCl, 1 mM MgCl2, 1 mM EGTA, 0.5% NP-40, 10% glycerol, 10 mM Na2HPO4, and 1 mM dithiothreitol). The cell extracts (500 µg) were diluted with the lysis buffer containing 0.1% NP-40 and precleared by incubation with 5 µg of rabbit immunoglobulin G (IgG) and 50 µl of protein A-agarose at 4°C for 2 h. The precleared cell extracts were incubated with 3 µg of polyclonal anti-Flag antibodies (Ab) (Sigma) at 4°C for 3 h, followed by incubation with protein A-agarose at 4°C for 2 h. After washing five times with NETN buffer (100 mM NaCl, 1 mM EDTA, 1 mM Tris-HCl [pH 8.0], 0.5% NP-40, and 1 mM dithiothreitol) at room temperature for 5 min, bound proteins were resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) followed by Western blotting with the anti-Myc Ab (Santa Cruz Biotechnology). To perform reciprocal experiments, the cell extracts were precleared by incubation with 5 µg of mouse IgG and protein A-agarose, followed by coimmunoprecipitation with 3 µg of monoclonal anti-Myc Ab and protein A-agarose. After extensive washes with NETN buffer, the bound proteins were analyzed by Western blotting with the anti-JMJ Ab that was characterized previously (22).
To map the protein-protein interaction domains between JMJ and Nkx2.5 or GATA4, GST pull-down assays were performed as described previously (26). The GATA4 mutant constructs (see Fig. 6C) are as follows. In the N-terminal zinc finger point mutant, cysteine residues at 236 and 239 were replaced by serine residues (C236S and C239S). The N-terminal zinc finger deletion mutant consists of amino acids 1 to 213 and 242 to 440. The C-terminal zinc finger point mutant contains a C290S mutation (26).
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RESULTS |
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To investigate whether JMJ binds to any of the A/T-rich sequences in the ANF enhancer-promoter region, GMSA were performed (Fig. 2A). Each of six A/T-rich oligonucleotides was labeled with 32P and incubated with GST-JMJ 529-792, the DNA-binding domain (DBD) of JMJ (22). JMJ showed stronger binding to two of the sequences, located at bp –580 and –110, in a dose-dependent manner, than to the A/T-rich sequences located at bp –405 and –265. To determine whether these two A/T-rich sequences mediate the repression function of JMJ in vivo, reporter plasmids were constructed by inserting the A/T-rich oligonucleotides upstream of the SV40 promoter linked to luciferase in the pGL3-promoter vector (Promega). The reporter plasmids, containing an A/T-rich sequence at bp –110 in the ANF promoter in the forward and reverse directions, were designated –110A/T Fw-pGL3 and –110A/T Rv-pGL3, respectively. When cotransfected (Fig. 2B), JMJ repressed both –110A/T Fw-pGL3 and –110A/T Rv-pGL3 by about 50%. Regardless of its orientation, the –110A/T sequence could mediate the transcriptional repression activity of JMJ. The enhancer mediates transcriptional activity regardless of its orientation. The repression function of JMJ was specific to the DNA binding of JMJ, because JMJ did not have any effect on transcriptional activity of the pGL3-promoter vector. JMJ repressed expression of the reporter genes containing –580 A/T-rich sequence in the forward and reverse directions (–580A/T Fw-pGL3 and –580A/T Rv-pGL3) at a level similar to –110A/T-pGL3 (data not shown). JMJ also repressed the reporter gene containing the weaker binding site of JMJ, located at bp –405 or –265, by about 30% (data not shown). These data suggest that JMJ may mediate the repression of ANF expression via these binding sites.
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It has been shown that JMJ is expressed in the heart (27, 43), as are Nkx2.5 and GATA4. To confirm these protein-protein interactions in cardiomyocytes, we also performed coimmunoprecipitation experiments using mouse heart extracts. However, the protein-protein interaction between JMJ and Nkx2.5 or GATA4 could not be confirmed by the conditions we employed, possibly due to the low expression level of each factor.
The C-terminal part of homeodomain in Nkx2.5 physically interacts with the DBD of JMJ. To map the protein-protein interaction domain between Nkx2.5 and JMJ, GST pull-down assays were performed (Fig. 5). Various 35S-labeled Nkx2.5 wild type and mutants were translated in vitro (Fig. 5A) and incubated with GST-wild-type JMJ (Jwt) or GST-JMJ 529-792 that contains the DBD of JMJ (Fig. 5B). A schematic diagram of Nkx2.5 mutants and summary of the binding results are shown in Fig. 5C. The Nkx2.5 wild type and the C-terminal deletion mutants, Nkx2.5 with a deletion of amino acids (aa) 1 to 230 or 1 to 199 (N 1-230 or N 1-199, respectively), interacted well with JMJ (lane 1 in Fig. 5B). When the C-terminal part of the homeodomain was deleted (Nkx2.5 1-182), the interaction was abolished (lane 4 in Fig. 5B). The reciprocal experiments were performed to map the interaction domain of JMJ. The GST-Nkx2.5 protein coupled to agarose beads was incubated with the in vitro-translated 35S-JMJ (Fig. 5D). Jwt (Fig. 5E, lane 1) and the C-terminal-containing mutant, JMJ 529-1234 (lane 3), interacted well with GST-Nkx2.5, but JMJ 1-528 did not (lane 2). The binding results are summarized in Fig. 5F. These data indicate that the DBD of JMJ (aa 529 to 792) mediates the interaction with Nkx2.5.
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JMJ represses the reporter gene containing the Nkx2.5- or GATA4-binding consensus sequence. We then investigated whether JMJ represses the Nkx2.5- or GATA4-dependent activation via a DNA-binding-independent mechanism. Cotransfection assays were performed by using the reporter genes containing either the Nkx2.5-binding consensus site, A20-TATA-Luc (10), or the GATA4-binding site, GATA4-TK-Luc (46). These reporter genes do not contain the DNA-binding site of JMJ. As shown in Fig. 7A, the A20 reporter gene was activated when cotransfected with Nkx2.5. Wild-type JMJ (Jwt) significantly repressed this Nkx2.5-dependent activation by 53% (46.2- versus 21.5-fold activation). The N-terminal part of JMJ (Jnt; aa 1 to 528) did not seem to repress the A20 reporter gene. Jnt does not contain the protein-protein interaction domain with Nkx2.5 and GATA4, but it contains the transcriptional repression domain. In contrast, the activation of the reporter gene by Nkx2.5 was markedly repressed with the coexpression of Jct, where the JMJ C-terminal aa 529 to 1234 is fused to the nuclear localization signal aa 1 to 130 (22). Jct contains the protein-protein interaction domain for Nkx2.5 (Fig. 5) and GATA4 (Fig. 6), but does not contain the transcriptional repression domain of JMJ. These data suggest that the protein-protein interaction domain of JMJ is required for most of the repression activity.
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It is possible that JMJ may compete with Nkx2.5 or GATA4 at their DNA-binding sites. However, our GMSA experiments (data not shown) indicated that JMJ bound to neither the NKE- nor the GATA-binding sequence identified in the ANF promoter (9, 26). The oligonucleotide sequences of the probes are described in Materials and Methods. In addition, the JMJ protein did not decrease the DNA-binding activity of Nkx2.5 or GATA4 to its own binding site when JMJ was coincubated with Nkx2.5 or GATA4 (data not shown). Therefore, it is unlikely that JMJ competes with Nkx2.5 or GATA4 at their DNA-binding sites, resulting in repression of the target gene expression.
JMJ does not interfere with the interaction between Nkx2.5 and GATA4. It has been reported that Nkx2.5 and GATA4 physically associate and cooperatively activate transcription of the ANF gene (9, 26). Because our data show that JMJ can interact with both Nkx2.5 and GATA4, we examined whether JMJ interferes with the physical interaction between Nkx2.5 and GATA4 (Fig. 8), which may lead to a decrease in their synergistic cooperation for ANF activation. 35S-labeled GATA4 preincubated with an excess amount of JMJ was then pulled down with GST-Nkx2.5, followed by SDS-PAGE and autoradiography. If JMJ interferes with the interaction between GATA4 and Nkx2.5, GST-Nkx2.5 would not efficiently pull down 35S-GATA4. When 35S-GATA4 (Fig. 8, lane 1) was preincubated with increasing amounts of cell extracts with JMJ overexpressed (lanes 2 and 3), GST-Nkx2.5 interacted with 35S-GATA4 as efficiently as with the control cell extract (lane 4). Similarly, 35S-Nkx2.5 (lane 6) preincubated with increasing amounts of JMJ (lanes 7 and 8) retained its ability to interact with GST-GATA4 as well as with control cell extracts (lane 9). These interactions were specific since neither 35S-GATA4 nor Nkx2.5 was pulled down by beads of GST alone (lanes 5 and 10). Although it is not possible to calculate the exact amount of each protein in the reaction, we preincubated minimal amounts of 35S-GATA4 or 35S-Nkx2.5 with large excess amounts of JMJ extracts as evidenced by Western blotting (data not shown) to saturate 35S-GATA4 and 35S-Nkx2.5. Therefore, it is unlikely that JMJ inhibits the physical interaction between Nkx2.5 and GATA4.
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DISCUSSION |
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Atrial natriuretic factor (ANF) is an important hormonal mediator of body fluid and electrolyte balance in both the normal and hypertensive states of mammalian species (7, 34). During normal development, ANF is expressed in both the atrial and ventricular chambers of the embryonic heart (48). Near birth, expression of ANF in the ventricular compartment decreases significantly, leading to the atrial-specific expression of the ANF gene in the normal adult heart. However, in response to increased demands for cardiac muscle work, cardiac muscle is activated by hypertrophic stimulation, which results in reactivation of the ANF gene expression in the ventricle. This reactivation of ANF is a hallmark for inducible gene expression in hypertrophied cardiac muscle cells (7, 34). An understanding of induction or repression of ANF expression will also provide valuable insights into the mechanism of hypertrophic changes of ventricle cells in the heart.
Regulation of ANF expression is controlled primarily at the transcriptional level. The transcription factors involved in activation of ANF expression include Nkx2.5, GATA4, MEF2, PitX2, and Tbx5 (3, 10, 12, 26, 31), which bind to their cis elements in the ANF enhancer region. In contrast, molecular mechanisms that repress ANF expression have not been well characterized. Several repressors of the ANF gene have been recently reported. For example, Tbx2, a Tbx isoform, inhibits ANF expression in the atrioventricular canal (14, 47). HOP and FOG2 inhibit ANF expression by interacting with SRF (5, 37) and GATA4 (39, 42), respectively. Our present data, together with the observation that JMJ-knockout mutant mice showed elevated levels of ANF expression in the late-stage embryonic ventricle compared to that of wild type (27), demonstrate that JMJ mediates down-regulation of ANF expression at the late embryonic stage of the ventricle. Since the expression level of JMJ is increased in the ventricle as it develops (27, 43), it is plausible that an increased amount of JMJ in the ventricle of the late-stage embryo results in repression of ANF expression.
GMSA indicates that JMJ binds to at least two A/T-rich cis elements in the ANF enhancer in vitro (Fig. 2A). JMJ inhibits expression of the reporter genes that contain these A/T-rich sequences (Fig. 2B). However, these cis elements do not seem to play a major role in JMJ-dependent repression of ANF expression, since JMJ inhibits activities of the ANF reporter genes where all or some of these A/T-rich sequences are deleted (Fig. 3B). The JMJ binding site located at bp –580 is particularly interesting, because this element has been demonstrated to mediate the up-regulation of ANF expression during cardiac myocyte hypertrophy (15) and also binds weakly to MEF2 (31). The transacting factor that binds to this site during cardiac hypertrophy has not been identified. Therefore, JMJ may be a putative therapeutic factor that prevents the reexpression of ANF in hypertrophic hearts by binding to the A/T-rich sequence at bp –580 in the ANF enhancer.
Our data suggest that the protein-protein interactions of JMJ with Nkx2.5 and GATA4 are essential in mediating the repression function of JMJ. Specifically, we mapped the protein-protein interaction domain of JMJ to a region between aa 529 and 792 (Fig. 5 and 6), which overlaps with the previously identified DBD of JMJ (22). It is interesting that JMJ interacts with the N-terminal region of GATA4 between aa 1 and 181, which is the transactivation domain of GATA4. Therefore, the physical association of JMJ with GATA4 may lead to the inhibition of the transcriptional activity of GATA4. The interaction site of GATA4 with JMJ is rather unusual, because the zinc finger region of GATA4 is known to serve as a protein interaction domain. For instance, the C-terminal and N-terminal zinc finger regions of GATA4 interact with Nkx2.5 (9, 26) and FOG-2 (39), respectively. The DBD region of JMJ (aa 529 to 792) is essential for interacting with Nkx2.5; therefore, this region seems to serve as a protein-protein interaction domain of JMJ. The C-terminal part of the homeodomain in Nkx2.5 mediates the interaction with JMJ and also mediates interaction with GATA4 to synergistically activate ANF expression (9, 26). Because JMJ interacts with Nkx2.5 and GATA4 interacts with Nkx2.5 via the same interaction domain, JMJ may interfere with the interaction between Nkx2.5 and GATA4. Therefore, we investigated by GST pull-down assay whether JMJ inhibits the physical association of Nkx2.5 with GATA4. As shown in Fig. 8, JMJ does not seem to interfere with the physical association between Nkx2.5 and GATA4 under the conditions we employed.
JMJ appears to repress ANF activation via protein-protein interactions with Nkx2.5 and GATA4, because Jnt, the JMJ mutant that does not contain the protein-protein interaction domain, lost most of its repression activity as shown in Fig. 7. In addition, Jct, which contains the protein-protein interaction domain, retains most of its repression activity. To exclude the possibility that Jnt contains an additional low-affinity protein interaction domain(s), several short JMJ mutants (such as aa 1 to 130, 1 to 220, 1 to 377, and 130 to 220) were subjected to a GST pull-down assay using GST-Nkx2.5 or GST-GATA4. However, none of the short fragments of JMJ bound to Nkx2.5 or GATA4 in vitro (data not shown).
JMJ contains a homologous region to the DNA-binding domain of the ARID transcription factor family. The members of this gene family include the B-cell-specific transactivator Bright (16) and the dead ringer gene product of Drosophila (13). JMJ has other motifs homologous to yeast SWI1, which mediates transcriptional activation (36), and two retinoblastoma-binding proteins (11), which bind to a cell cycle regulator, pRb. Thus, JMJ may also be involved in cell proliferation and differentiation via interaction with the cell cycle regulator pRb or with pRb-related factors, such as p107 (50). It would also be interesting to identify the novel factors that may mediate the physiological and transcriptional regulatory functions of JMJ.
JMJ may regulate expression of other genes, since jmj knockout caused embryonic lethality in mice and JMJ is expressed widely throughout development (27, 33, 41). The ANF gene may be one of the endogenous target genes of JMJ in the ventricles of last-stage embryos, and there may be other target genes of JMJ in different tissues and at different developmental stages. Indeed, our study of transcriptional repression function of JMJ in the heart is supported by a recent paper, which was published while the present study was in preparation, describing how JMJ represses cyclin D1 expression in the heart (43). Taken together, these studies demonstrate that JMJ is a DNA-binding trans-acting factor involved in a transcription factor cascade in heart development.
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ACKNOWLEDGMENTS |
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This work was supported in part by grants from NIH (HL67050) and the American Heart Association (0030002N) to Y. Lee and a grant from NIH (HL67724) to J. Sadoshima.
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FOOTNOTES |
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