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Department of Biochemistry, Hebrew University Medical School, Jerusalem, Israel,1 Department of Oncology, Hadassah Medical Center, Jerusalem, Israel2
Received 7 August 2006/ Returned for modification 9 October 2006/ Accepted 16 March 2007
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Mitf regulates gene transcription by binding to E-box elements in the 5'-flanking regions of Mitf-responsive genes (23). Like other DNA-binding proteins, the transcriptional activation of Mitf is influenced in a complex manner by different intracellular proteins. For example, in vitro studies have indicated that Mitf can form heterodimers with the four related family members TFEB, TFEC, TFE3, and USF2 (10, 28). In our efforts to explore the role played by this transcription factor in the growth, differentiation, and maturation of mast cells, we recently identified two inhibitors of Mitf transcriptional activity, Hint (32) and protein inhibitor of activated STAT3 (PIAS3) (16).
Mitf is regulated at both the transcriptional and posttranscriptional levels. Mitf is transcribed from several alternative promoters, giving rise to various splice isoforms with potentially distinct biological functions (Fig. 1A) (reviewed by Steingrimsson et al. [33]). While exon 1m is melanocyte specific, and exon 1h is extensively used in the heart (11), other exons (such as 1a) are more widely expressed. These exons are widely spaced in the genomic DNA and are expressed from different promoters (M, A, and H). The regulation of Mitf expression has only been studied in depth in melanocytes, and very little is known about the regulation of its expression in other cells. The expression of Mitf isoforms has been investigated in several mast cell lines (29, 36). Expression of Mitf-MC and Mitf-H was detected in the C57 mast cell line and in bone marrow-derived mast cells (BMMC) (36), while spleen-derived mast cells expressed Mitf-E and Mitf-M (29), and peritoneal mast cells expressed mainly Mitf-M. However, the regulation of Mitf isoforms by physiological stimuli has never been explored. Also, the biological function of the different Mitf isoforms is as yet unclear, although it has been shown that Mitf-M has much greater activation potential of the tyrosinase promoter than Mitf-MC in NIH 3T3 cells (36).
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Since it is known that only the Mitf-H isoform is expressed in the heart, this seemed an ideal system to explore the importance of cell context on the activity of the different Mitf isoforms by comparison to mast cells in which a variety of isoforms are expressed.
Our results indicate tissue-specific differences in the expression and regulation of Mitf isoforms, depending on the physiological stimuli. Furthermore, we found that the transcriptional activation potential of the different Mitf isoforms depends on the cell type and the DNA target. In addition, we have demonstrated that Mitf is expressed in cardiomyocytes and regulates the expression of myosin light-chain 1a (MLC-1a).
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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BMMC were either triggered with 1 µg/ml anti-2,4-dinitrophenol (DNP) immunoglobulin E (IgE) monoclonal antibody alone overnight (SPE-7; Sigma-Aldrich Corp., St. Louis, MO) or first sensitized with IgE overnight and then challenged with 300 ng/ml DNP for 2 h. IgE antibody was ultracentrifuged before use to remove aggregates.
Mice. All mouse lines were held and propagated in a specific-pathogen-free environment. Mitfsp/sp and Mitfsp/ce mice were kindly provided by Lynne Lamoreux from the College of Veterinary Medicine, Texas A&M University, and bred to produce sp/sp and ce/ce mice for experiments. The Mitf encoded by the mutated mouse allele (ce/ce) lacks the Zip domain of Mitf because of a stop codon between the HLH and Zip domains (34). VGA-9-tg/+ mice were kindly provided by H. Arnheiter (NIH, Bethesda, MD) and were propagated by heterozygous crossing. Mice carrying the tg/tg mutation have an insertion of approximately 50 copies of a transgene integrated upstream of the Mitf-M promoter and are unable to express Mitf (11). Normal littermates of ce/ce mice were distinguished by coat color. Normal littermates of tg/tg mice were determined by genomic DNA extraction from tails and subsequent PCR analysis.
PCR amplification. Total RNA was prepared using TRI reagent (Sigma, Saint Louis, MO). For PCR analysis, RNA was reverse transcribed using Expand reverse transcriptase (Roche Applied Science, Mannheim, Germany). Primers were used to amplify the region between alternative exon 1 and the constant exon 2 or 5 of Mitf. The resulting PCR products were electrophoresed on an agarose gel. The primers used for Mitf amplification were as follows: exon 1a, 5'-AAGTCGGGGAGGAGTTTCAT-3'; exon 1e, 5'-TCACAGAGGTTAGTAGGTGGATGGG-3'; exon 1h, 5'-GGCGCTTAGATTTGAGATGC-3'; exon 1m, 5'-GAGGACTAAGTGGTCTGCGG-3'; exon 2, 5'-TGTGGTACTTGGTGGGGTTT-3'; and exon 5, 5'-GGACAGGAGTTGCTGATGGT-3'. The presence of exon 6a was analyzed by PCR amplification and subsequent scanning and densitometry on ImageMaster VDS-CL using TINA 2.10 software. The primers used were exon 5 (5'-ACCATCAGCAACTCCTGTCC-3') and exon 7 (5'-TAGCTCCTTAATGCGGTCGT-3').
Real-time quantitative PCR. Candidate Mitf-responsive genes were measured using real-time quantitative PCR. Total RNA was extracted from hearts of wild-type, ce/ce, and tg/tg mice. mRNA levels of various genes were quantified by SYBR green incorporation or by Taqman probe (SYBR green PCR master mix and Taqman master mix; Applied Biosystems, Foster City, CA) on the ABI Prism 7000 sequence detection system (Applied Biosystems).
The primers used for gene amplification for real-time PCR were as follows: ß-actin sense, 5'-CCTGATCCACATCTGCTGGAA-3'; ß-actin antisense, 5'-ATTGCCGACAGGATG CAGAA-3'; MLC-1a 574F, 5'-GAGGTGGAGCAGCTGTTGTCT-3'; and MLC-1a 714R, 5'-CGCTGTGGATCTCTTGC TTTC-3'. The primers used for amplification of Mitf isoforms are described in Table 1.
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The MLC-1a promoter was amplified using PCR of genomic mouse DNA, and the fragment from –638 to +58 was excised using PstI and SacI (New England Biolabs, Inc.) and ligated into a pSP72 vector (Promega Co., Madison, WI) containing a luciferase reporter gene. Mutations of MLC-1a promoter were generated using the QuickChange mutagenesis kit (Stratagene, LaJolla, CA) with the following primers: E3 mutant sense, 5'-GATAATACTGAGATGTGAGTTGCACCCGGCTGGTGTC-3'; E3 mutant antisense, 5'-GACACCAGCCGGGTGCAACTCACATCTCAGTATTATC-3'; E2 mutant sense, 5'-GTCAGCTGCACCCGGGTGTTGTCTCTTCCTTTTATAG-3'; and E2 mutant antisense, 5'-CTATAAAAGGAAGAGACAACACCCGGGTGCAGCTGAC-3'.
N termini of Mitf-H and Mitf-MC were amplified by PCR from cDNA derived from BMMC and cloned into a pcDNA-Mitf-M expression vector. The mMCP-6 promoter reporter vector was kindly provided by Y. Kitamura (Osaka, Japan), and the tyrosinase reporter was kindly provided by David Fisher.
Transient cotransfection and luciferase assay. NIH 3T3 cells (2 x 105) were cotransfected using Transfast reagent (Promega Co.) with 0.1 µg of wild-type or E23-mutated MLC-1a-pSPLuc reporter and 0.1 µg of pcDNA-Mitf wild-type or ce/ce mutant Mitf. NIH 3T3 and H9C2 cells were similarly cotransfected with 0.1 µg of various Mitf isoform expression vectors and either mMCP-6, tyrosinase, or MLC-1a reporter. The cells were incubated in 24-well plates for 48 h. The cells were lysed and assayed for luciferase activity. The luciferase activity was normalized to the total protein concentration.
Nucleofection of RBL cells. RBL cells (5 x 106) were used in luciferase assay experiments. Cells were transfected using Nucleofector Technology solution R and program T-20 (Amaxa Biosystems, Amaxa GmbH, Cologne, Germany). Cells were transfected with 1 µg of different luciferase reporter genes of MITF (mMCP-6 and tyrosinase) and 1 µg of the different Mitf splicing variants (M, MC, and H). The cells were incubated in plates for 24 h, lysed, and assayed for luciferase activity. The luciferase activity was normalized to the total protein concentration. The ratio was expressed as the relative luciferase activity.
EMSA. For the electrophoretic mobility shift assay (EMSA), cold, mutated, and hot probes were synthesized by PCR amplification of the following primers: E23F, 5'-GGATTGGTGGCTCAAACCTGG-3'; E23R, 5'-AGAGACACCAGCCGGGTGC-3'; E1F, 5'-TCTCTTCCTTTTATAGTCAGCAGC-3'; E1R, 5'-TAGGAGCCCCCACAGAGG-3'; E4F, 5'-CCTGCGGTTGGGAGAGTGG-3'; and E4R, 5'-AGCCCTGAAGCAACAGCTGG-3'.
E23 was used as a probe by labeling with [32P]dCTP. Cold E23, including mutations in E23, E1, and E4 were used for competition with 5,000 cpm of radiolabeled E23 on binding to 10 µg of glutathione S-transferase (GST)-Mitf or GST-ce/ce mutant Mitf. NIH 3T3 and H9C2 nuclear extracts were prepared as previously described (38). Binding and running were performed as previously described (16).
ChIP assay. The chromatin immunoprecipitation (ChIP) assay was performed as follows. H9C2 cells were treated with formaldehyde for protein-DNA cross-linking, and chromatin was extracted and then sonicated to give an average size of 300 to 3,000 bp. Chromatin was incubated with either affinity-purified anti-Mitf antibody or preimmune IgG serum from the same rabbit. Immunoprecipitation was performed overnight at 4°C with rotation. After washing and elution, DNA was purified by phenol-chloroform extraction and resuspended in 20 µl of Tris (10 mM)-EDTA (1 mM) buffer. DNA solution (2 µl) was used as a template for 27 cycles of PCR amplification with the following primers: forward, 5'-GGAGGACGAACTGGTGACAA-3'; and reverse, 5'-GCCTTCCCCTGCTTTTATTC-3'.
Prediction of Mitf binding sites. Twenty-one previously published Mitf binding sites were used to build a nucleotide distribution matrix, which was processed by MatInd (30). The resulting output was used by MatInspector to scan sequences for Mitf binding sites, with a core similarity threshold of 0.80 and matrix similarity threshold of 0.85.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Analysis of the different Mitf isoforms expressed in BMMC was performed using real-time PCR-specific 5' primers and 3' primers from the common exon 1b. The level of the E isoform was very low in both resting and activated BMMC (less than 3% of the total Mitf). In resting mast cells (control), both the MC and H isoforms were expressed (Fig. 2A and B). Mitf-MC isoform expression was repressed by IgE alone, while activation with IgE and antigen (IgE plus DNP) increased its expression (Fig. 2A). In contrast, IgE alone increased the expression of the Mitf-H isoform, while activation with IgE plus DNP decreased this isoform's expression (Fig. 2B). Overall, IgE alone caused a shift to the Mitf-H isoform, while IgE plus DNP caused a shift to the Mitf-MC isoform (Fig. 2C).
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RI by either IgE followed by DNP (IgE plus DNP) for 4 h or activation of mast cells by stem cell factor (SCF), the ligand of c-kit receptor, significantly reduced the expression of the Mitf-(+) isoform. H9C2 cardiomyoctes also express both the Mitf-(+) and Mitf-(–) isoforms (Fig. 2E). Cells grown in growth medium express the Mitf-(–) isoform, but when these cells were cultured in serum-free medium for 6 h, the Mitf-(+) isoform became dominant. We were unable to detect a similar shifting of Mitf isoforms in melanocytes, where the Mitf-(+) isoform was dominant under all conditions tested, constituting about two-thirds of all transcripts (data not shown).
Melanocytes and cardiomyocytes express specific Mitf isoforms (M and H, respectively), while mast cells express a variety of isoforms, which are switched according to different physiologic stimuli, such as the aggregation of FcRI. Switching between Mitf-(+) and Mitf-(–) isoforms was detected in both mast cells and cardiomyocytes but not in melanocytes.
The identification of a cardiac-specific target for Mitf, MLC-1a. Since we have demonstrated that the Mitf-H isoform is expressed in cardiomyocytes (37), and it seems to be the only isoform expressed, we were interested in studying the impact of different isoforms on the expression of cardiomyocyte-specific target genes in contrast to mast cell-specific targets in both cell types. However, since no cardiac-specific targets of Mitf have been described so far, we set out to find such a target.
Since several bHLH-Zip transcription factors were shown to regulate the expression of the various myosin chains (4, 20, 27), the mRNA levels of the different myosin heavy and light chains in the hearts of wild-type and Mitf-mutated mice were determined using real-time PCR. No significant differences were apparent for either myosin heavy chains or for the regulatory myosin light chains. However, the level of MLC-1a, which is specifically expressed in the heart and is known to be an important regulator of force generation (6), was significantly decreased in both tg/tg and ce/ce Mitf-mutated mice (P < 0.01, n = 14, and P < 0.01, n = 13, respectively) (Fig. 3).
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The E-box element E23, located at –128, was able to bind wild-type Mitf, and competition with cold E23 completely abolished this binding (Fig. 4B). Furthermore, E23 very weakly bound the ce/ce mutant Mitf (Fig. 4B). E1 and E4 competed weakly with E23. Using NIH 3T3 nuclear extracts, we were able to detect a band in cells overexpressing Mitf-H but not in cells that were transfected with an empty vector. To further verify Mitf binding to the MLC-1a promoter, supershift experiments were carried out on H9C2 nuclear extracts using polyclonal anti-Mitf antibody directed against the common C terminus. The E23-DNA complex was supershifted by anti-Mitf antibody but not by the preimmune serum of the same rabbit (Fig. 4C). We next used cold competitors with mutations in either E-box E2 (E2), E3 (E3), or both (E23). The mutated E3 oligonucleotide only partially competed with the normal E23 probe, while E2- and E23-mutated olingonucleotides were unable to compete (Fig. 4D), indicating that the double-E-box E23 is indeed necessary for the binding of Mitf.
Using the ChIP assay, endogenous Mitf from cardiomyocytes was detected at the MLC-1a promoter in vivo (Fig. 4E).
The transcriptional activity of Mitf on MLC-1a promoter was then determined by construction of a pSP72 reporter plasmid which harbored the –638 to +57 fragment from MLC-1a promoter upstream of the luciferase reporter gene. NIH 3T3 fibroblasts were cotransfected with either full-length wild-type or ce/ce mutant Mitf expression vectors and the MLC-1a promoter reporter construct. Wild-type Mitf was able to activate the MLC-1a promoter approximately four times more efficiently than ce/ce Mitf (Fig. 4F).
E-boxes E2 and E3 in the E23 element were point mutated to gTGtTG and gAGtTG, respectively. NIH 3T3 fibroblasts were cotransfected with the three mutant MLC-1a promoters or wild-type promoter with Mitf expression vector. Mitf was able to activate the wild-type MLC-1a promoter roughly fourfold more than the mutated MLC-1a promoters (Fig. 4G).
Thus, real-time PCR, EMSA, ChIP, and transient transfection assay results indicate that Mitf regulates MLC-1a expression.
Activation of Mitf target genes by different Mitf isoforms in mast cells. The Mitf isoforms were cotransfected into NIH 3T3 cells with luciferase reporter vectors of the mast cell protease mMCP-6 and the melanocyte-specific tyrosinase (Fig. 5A and B). The MC isoform had the weakest transactivation potential for both promoters, while the H isoform caused two- to threefold-stronger transactivation. In addition, in contrast to the observation that M isoform transactivation of the mMCP-6 promoter was similar to that of the H isoform, M isoform activation of the tyrosinase promoter was over 10-fold greater than its activation by both the MC and the H isoforms. We observed slightly different results in mast cells. Tyrosinase activation in mast cells was similar to that in NIH 3T3 cells (Fig. 5C and D). However, whereas the mMCP-6 promoter in RBL cells was similarly activated by the MC and H isoforms, activation by the M isoform was threefold greater. The activation of the tyrosinase promoter by the various Mitf isoforms in mast cells showed the same pattern as in NIH 3T3 cells, whereas the mMCP-6 activation pattern was dependent on the cell type. These results also indicate that while Mitf-M and Mitf-MC transactivation potential is not influenced by cell type, as previously described (36), Mitf-H activity is sensitive to cell type, suggesting a new role for the differential splicing of Mitf. Thus, Mitf transactivation potential is dependent on cell type, DNA targets, and the isoform of Mitf, with Mitf-H being sensitive to the cell type.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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We have studied the regulation of Mitf isoforms in several cell types. Melanocytes and cardiomyocytes express specific Mitf isoforms (M and H, respectively), but mast cells can express a variety of isoforms (MC, E, H, A, and M), and isoform expression is determined by the cell type and is dependent on physiological stimuli. Mast cells can also down-regulate the expression of exon 6a as a result of activation with either IgE plus DNP or SCF. Similarly, up-regulation of exon 6a was detected in cardiomyocytes in response to serum deprivation but was not detected in melanocytes.
Although the splicing variants both including and excluding the 18-bp exon 6a (Fig. 1A) have been extensively described in the literature, the role of exon 6a splicing still has to be investigated. The splicing of exon 6a does not affect either sumoylation of Mitf (18) or its phosphorylation by extracellular signal-regulated kinase (ERK) (19). Furthermore, while binding of Mitf without exon 6a to DNA as a homodimer is only slightly decreased, there is no effect on its binding as a heterodimer (10). An indication of the physiological role of these splicing products was recently provided (3). Mitf-(+) was shown to have a strong inhibitory effect on cell proliferation by transfection of Mitf-M into 293HEK cells. This activity seems not to be related to Mitf transcriptional activity, and deletion of the N terminus resulted in loss of the Mitf-(+) inhibitory effect. Depletion of Mitf-(+), therefore, might account in part for the increased proliferation of mast cells exposed to SCF (reviewed by Bischoff and Sellge [2]).
Our results indicate that while the M isoform had a high and constant transcriptional activity in all cell types used in our study, particularly for the tyrosinase promoter, and while the activity of the MC is consistently lower, the activity of the H isoform is dependent on cell type. Furthermore, activity of the H isoform is dependent on the presence or absence of the alternative exon 6a in cardiomyocytes, but not in NIH 3T3 cells, indicating the involvement of cell-specific regulators in the function of Mitf isoforms. Thus, we describe here for the first time a role for the alternative exon 6a in the regulation of Mitf's transcriptional activity. This role seems to be cell context sensitive, indicating that a protein-protein interaction might be required to exert this fine-tuning effect.
The M isoform includes only 11 amino acids upstream of the common exon 2, while all other isoforms include at least the 83 amino acids of exon 1b and a variable N terminus of 20 to 40 amino acids. These alternate N termini could enable Mitf to become sensitive to cell-specific inhibitors and activators and to the presence or absence of the alternatively spliced exon 6a.
Sequence analysis of exon 1b revealed a glutamine-rich domain containing 20 glutamine residues, most of which are absent from the M isoform, but are present in all other Mitf isoforms, including the E isoform, which lacks a part of exon 1b. This glutamine-rich domain is highly conserved between species (Fig. 7) and is predicted to assume a coiled-coil structure. Glutamine-rich domains can act as transcriptional activators (7) or could participate either in cis or in trans transcriptional inhibition (5). Thus, Mitf gains greater complexity in the regulation of its various target genes in different cells, enabling it to fine-tune its response to physiological stimuli. The presence or absence of the glutamine-rich domain together with the myriad of splicing options of Mitf (8) could not only enable great variety in the activation of the different Mitf targets by Mitf but also could permit Mitf to function as a transcriptional repressor of related transcription factors. The transcription factor Sp3, for example, carries an inhibitor domain that not only inhibits the Sp3 glutamine-rich domain mediated transactivation but also represses the activity of its family member Sp1 (5). Whether all MITF transcripts are translated in vivo remains to be determined. However, the shortness of the different N termini presents a problem in designing efficient specific antibodies and hinders answering this question.
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Our results clearly demonstrate that the various Mitf isoforms are regulated by physiological stimuli and that this enables refined control of target gene expression through a cell context and promoter context combinatory effect. Further investigation is needed in order to fully decipher the role played by Mitf and its various isoforms in the physiology of the heart, mast cells, and possibly other cell types.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Published ahead of print on 16 April 2007.
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