ABSTRACT
Sp1 is a ubiquitous activator of numerous TATA-containing and TATA-less promoters within the human genome. This transcription factor is distinct from several other mammalian activators because it cannot stimulate transcription of reporter genes when ectopically expressed in Saccharomyces cerevisiae. Here we report that in cultured cells from Drosophila melanogaster human Sp1 efficiently activates transcription from synthetic promoters containing TATA boxes, but not from promoters that contain an initiator instead of a TATA box. The inability of Sp1 to activate initiator-mediated transcription did not result from inactivity of the consensus initiator element used for the experiments, as other initiator functions were conserved in Drosophila cells. Interestingly, a difference between the Drosophila and human TFIID complexes was found to be responsible for the selective inability of Sp1 to activate initiator-mediated transcription in Drosophila; in a complementation assay with a TFIID-depleted HeLa cell extract both the Drosophila and human TFIID complexes supported TATA-mediated transcription, but only the human complex supported initiator-mediated transcription. These results suggest that a species-specific interaction is required for activation of TATA-less promoters by Sp1, revealing a difference in transcriptional activation mechanisms between vertebrates and invertebrates.
Sp1 was isolated from HeLa cell extracts over 12 years ago as a sequence-specific DNA binding protein capable of activating transcription from the simian virus 40 (SV40) early promoter in a cell-free assay (1,2). Subsequent studies demonstrated that Sp1 contributes to activation of numerous viral and cellular genes (3-5). Because it was the first sequence-specific activator of pol II genes identified and because of its widespread role in regulating transcription the functional properties and biochemical activities of Sp1 have been analyzed in considerable detail.
The DNA binding activity of Sp1 is mediated by a zinc finger region near the C-terminus of the protein and transcriptional activation involves four distinct domains (6-8). The A and B activation domains near the N-terminus each contain a glutamine-rich region and an adjacent region rich in serines and threonines. When targeted to a promoter by a heterologous DNA binding domain these domains strongly activate transcription (see for example 9,10). The C and D activation domains, which flank the zinc finger region in the C-terminal half of the protein, activate transcription poorly by themselves, but augment the activities of the A and B domains (8). The D domain also acts in concert with the A and B domains to direct formation of Sp1 multimers, which are essential for synergistic activation of transcription (11-14).
During the past few years progress has been made towards an understanding of the mechanism by which Sp1 stimulates transcription. Like many activators Sp1 requires the transcription factor IID (TFIID) complex for efficient stimulation of transcription in vitro (15-18). Furthermore, Sp1 can directly stabilize binding of TFIID to core promoter elements (19). Physical interactions have been detected between Sp1 and three components of human TFIID: TBP, hTAFII130 and hTAFII55 (9,20-23). TBP and hTAFII130 interact with the glutamine-rich domains of Sp1, whereas hTAFII55 binds to the C-terminus (9,20-23). The functional relevance of the Sp1-hTAFII130 interaction has been supported by in vitro transcription experiments with reconstituted Drosophila TFIID subcomplexes, in which the Drosophila homolog of hTAFII130, dTAFII110, was found to play an essential role during Sp1 activation (24,25). Sp1 may also interact with other components of the pol II preinitiation complex (26).
Further insight into the functions of the Sp1 activation domains was recently provided by an analysis of their abilities to activate transcription through core promoters with different structures (10). This analysis revealed that the isolated glutamine-rich domains, when fused to a heterologous GAL4 DNA binding domain, possess a strong preference for a core promoter containing an Inr element; activation was not detected if the core promoter contained only a TATA box. In contrast, full-length Sp1 activated transcription with equal efficiency through core promoters containing either a TATA box or an Inr. Activation of a promoter containing only a TATA box apparently requires the combined functions of the N-terminal and C-terminal activation domains, revealing clear functional differences between the domains.
To investigate the mechanisms of Sp1 activation from different core promoters in greater detail we wished to ectopically express wild-type and mutant Sp1 proteins in cells that do not express an endogenous Sp1 protein. Since all mammalian cells express Sp1, we employed the Drosophila melanogaster SL2 cell line, which does not express the tissue-restricted Drosophila homolog of Sp1 (27). The SL2 cell line has been used successfully for several other studies of Sp1 (8,9,11,13), including the original analysis of the Sp1 activation domains. The unexpected results obtained from our analysis provide further insight into the mechanisms of transcriptional activation by Sp1, into the differences between TATA- and Inr-mediated transcription and into the evolution of the pol II transcription apparatus.
The basic reporter plasmids used for the transient transfection assays have been described previously (10). These plasmids contain multiple binding sites for GAL4 or Sp1 upstream of three different core promoters (Fig. 1) and a herpes simplex virus thymidine kinase (HSV-TK) gene. The plasmids used for in vitro transcription experiments are the same as plasmids II (TATA; 15), IV (TATA/Inr; 15), I (weak TATA/Inr; 15) and VI-c (Inr; 28), except that the Sp1 sites were deleted from VI-c. The expression plasmids for the full-length and mutant Sp1 proteins have been described previously (8,13). For simplicity we renamed some of the deletion mutants, with the name used here corresponding to the deleted domain: pPac0 is the expression vector lacking Sp1 sequences; [Delta]B, [Delta]A1, [Delta]A2, [Delta]Bc, [Delta]Bn, [Delta]D and [Delta]Dc are [Delta]A0, C2-2E, pPack, D23, D9, N619 and N636 respectively (8,13). The M21 and M37 substitution mutants described previously (9) were inserted into the context of the [Delta]A2 protein. The GAL4-Sp1 expression plasmid (10), the GAL4-ftzQ expression plasmid (29,30), the plasmids with variable spacing between TATA and Inr (31), the reverse TATA-Inr plasmid (31) and the plasmids with different sequences 25 bp upstream of the TdT Inr element (28) have been described previously. All plasmids were purified by column chromatography (Qiagen Inc.).
The human embryonic kidney cell line 293 and the Drosophila cell line SL2 were grown and transfected by the calcium phosphate method as described previously (8,10). The transfected human and Drosophila cells were incubated for 48 h at 37 and 25°C respectively and then total cytoplasmic RNAs were isolated by a Nonidet P-40 lysis method (28). Promoter strengths were analyzed by primer extension, using 30 µg RNA and a 20 nt primer complementary to a HSV-TK sequence (28).
In vitro transcription reactions with nuclear extracts derived from HeLa cells or Drosophila embryos (a kind gift from Dr Al Courey, UCLA) were performed as described previously (28,32) except the reactions with Drosophila extracts were incubated at 21°C. Each reaction contained 300 or 500 ng template and 100 µg extract. RNA transcripts were analyzed by primer extension as described (32). TFIID-depleted extracts were prepared by heat treatment of HeLa extracts at 47°C for 20 min (33). The epitope-tagged human and Drosophila TFIIDs were isolated by immunoaffinity chromatography as described (18,34).
The human Sp1 protein efficiently activates transcription in mammalian cells from synthetic promoters containing multiple Sp1 binding sites and either a TATA box, an Inr or both TATA and Inr elements (10,15,28,32). This result is reproduced in Figure 1A. In addition, a protein containing the GAL4 DNA binding domain fused to full-length Sp1 stimulates transcription of reporter plasmids containing multiple GAL4 binding sites upstream of the TATA, Inr or TATA-Inr core promoters (10). This result is reproduced in Figure 1B. The reporter plasmids used for these experiments contain multiple upstream binding sites for Sp1 (Fig. 1A) or GAL4 (Fig. 1B) upstream of the three different core promoters (Fig. 1, bottom) and a HSV-TK reporter gene. Forty eight hours after transfection of human 293 cells with the reporter plasmids alone (Fig. 1A) or with the reporter plasmids and a GAL4-Sp1 expression plasmid (Fig. 1B) total RNAs were isolated and analyzed by primer extension. (It should be noted that Figure 1B was derived from a much longer exposure than Figure 1A, resulting in the appearance of unactivated transcription signals.)
Interestingly, when the same reporter plasmids were tranfected into the Drosophila SL2 cell line in the absence and presence of a well-characterized Sp1 expression plasmid (pPacSp1; 8) the relative promoter strengths observed were strikingly different from those observed in the human cells. Although the transcripts directed by the TATA and TATA-Inr promoters were easily detectable (Fig. 1C, lanes 2 and 4), the transcripts directed by the Inr promoter were undetectable (lane 6), even with long exposures (data not shown). The selective inability of Sp1 to activate Inr-mediated transcription was confirmed by transfection of SL2 cells with increasing concentrations of the reporter plasmid (Fig. 2) or with increasing concentrations of the Sp1 expression plasmid (data not shown). In more than 20 experiments a specific primer extension signal has never been detected with the Inr reporter plasmid, despite consistently strong signals with this reporter in human cell lines. Similar results were obtained following transfection of SL2 cells with an expression plasmid for Sp3, a human protein that is closely related to Sp1 and that binds to the same DNA sequence element (35; data not shown).
The results in Figure 1D suggest that the TdT Inr functions properly in Drosophila cells. To confirm this hypothesis other properties of the consensus TdT Inr element were compared in human and Drosophila cells. To rule out potential contributions from specific activator proteins in vitro transcription experiments in nuclear extracts from HeLa cells and Drosophila embryos were employed. Unlike transfection experiments, the in vitro transcription experiments are sufficiently sensitive for detection of basal transcription directed by the isolated core promoter elements.
Figure 3A reveals that the basic properties of TATA and Inr elements are comparable in nuclear extracts from Drosophila and man. In both extracts the promoter containing the isolated TATA box led to the expected 70 nt cDNA product (Fig. 3A, lane 1; see also Fig. 3B, lane 1). [The bands above and below the specific TATA signal were observed in previous experiments (31) and are believed to be non-specific background bands.] The TATA-Inr promoter yielded the expected 79 nt product in both extracts (which is 9 nt longer than the 70 nt cDNA product because of the 9 bp Inr insertion). The TATA-Inr promoter was stronger than the TATA promoter in both extracts, although the degree of synergy between the TATA and Inr elements varied from experiment to experiment (Fig. 3A, lane 2; see also Fig. 3B, lanes 1 and 2). Specific transcription in both extracts was also directed by promoters containing the TdT Inr element downstream of weaker TATA sequences, one containing a reverse consensus TATA box, TTTATA (Fig. 3A, lane 3), and the other containing the sequence CATATG (Fig. 3A, lane 4). Very little transcription was directed by the promoter containing the TdT Inr element downstream of the G/C-rich sequence used for the experiments in Figure 1 (Fig. 3A, lane 5).
The results in Figure 1 reveal that Sp1 efficiently activates transcription in Drosophila cells from a promoter containing a consensus Inr combined with a strong TATA box, but not a consensus Inr lacking a TATA box (Fig. 1C). These results suggest that a strong TATA box is required for Sp1 activation. An alternative explanation, however, is that the G/C-rich sequence which replaces the TATA box in the -25 region of the Inr promoter strongly inhibits function of the Drosophila transcription machinery during Sp1-activated transcription. To distinguish between these possibilities promoters containing different sequences between -24 and -33 were analyzed in human and Drosophila cells (Fig. 4). As previously reported (28), all of the promoters direct efficient activated transcription following transfection into human 293 cells (Fig. 4A). The strengths of these promoters roughly correlate with the affinities of their upstream sequences for TBP (28). In striking contrast, Drosophila cells supported Sp1-activated transcription only from the promoter containing the strong consensus TATA box (Fig. 4B). These results demonstrate that the inability of Sp1 to activate Inr-mediated transcription in Drosophila is not restricted to promoters containing upstream regions with a high G/C content.
Our original goal in studying Sp1 in Drosophila cells was to develop an assay for defining the Sp1 domains required for activation of TATA- and Inr-mediated transcription. The results described above demonstrate that we cannot use Drosophila cells for this purpose. However, since the Inr enhances Sp1-activated transcription when the core promoter includes a TATA box, the Sp1 domains required for activation of the TATA promoter can be compared with the domains that allow the Inr to enhance TATA-mediated transcription.
Figure 5 shows the relative strengths of the TATA and TATA-Inr promoters when activated by several Sp1 mutants (8,13). In general, the effects of these mutations with the Sp1-TATA-Inr and Sp1-TATA promoters were similar to the effects observed previously with reporter plasmids containing multiple Sp1 sites upstream of natural core promoters with TATA boxes (8,13). Interestingly, with each of the mutants the ability of the Inr to enhance promoter strength was not strongly affected. For example, relative to wild-type Sp1 the [Delta]B mutation resulted in enhanced transcription from both promoters, with strong Inr activity maintained (Fig. 5, compare lanes 3 and 4 with 5 and 6). Strong Inr activity was also maintained with mutations that had little effect on promoter strength (e.g. [Delta]A1 and [Delta]Bn), as well as with mutations that reduced promoter strength ([Delta]A2, M21, [Delta]Dc and [Delta]D). [As expected, none of the Sp1 mutants stimulated transcription from the Inr promoter (data not shown).] These results suggest that the Sp1 domains required for TATA-mediated transcription cannot be distinguished from the domains required for Inr activity in a promoter that also contains a TATA box.
The results presented above demonstrate that in Drosophila cells Sp1 cannot activate transcription of a TATA-less promoter, even though the Inr element within this promoter is functional. These results could reflect an inability of a domain of Sp1 to be properly modified when expressed in Drosophila cells. Alternatively, it could reflect the absence of an essential event during Sp1 activation that involves the Drosophila general transcription machinery. The TFIID complex is an attractive candidate for the `defective' component of the Drosophila general transcription machinery because of its important role in mediating transcriptional activation (40).
To determine if TFIID is involved in the species specificity observed, we employed an in vitro complementation assay. HeLa nuclear extracts were depleted of TFIID activity by a standard procedure, which involves heat treatment at 47°C (33). As expected, the heat treatment abolishes the extract's ability to support transcription (Fig. 6, lanes 1-4). When highly purified human TFIID (18,19) was added to the extract strong transcription from the four promoters containing Sp1 binding sites was restored (lanes 5-8). The relative promoter strengths obtained were similar to those routinely observed with crude nuclear extracts (10,15). In contrast, when purified Drosophila TFIID was added to the extracts strong transcription was detected with the Sp1-TATA and Sp1-TATA-Inr promoters, but transcription was not detected with the Sp1-Inr promoter (lanes 9-12).
These results reveal an interesting species-specific difference between the human and Drosophila TFIID complexes. The most likely explanation for this difference is that Drosophila TFIID is unable to support Sp1 activation of the Inr promoter. Because we are unable to detect significant basal transcription from the Inr promoter in HeLa cell extracts, however, we cannot completely rule out the possibility that Drosophila TFIID possesses a more general defect in supporting Inr activity. Nevertheless, based on the in vivo evidence that the Drosophila defect is specific for Inr-mediated transcription stimulated by Sp1, the in vitro defect is also likely to be specific for Sp1 stimulation.
The data presented in this manuscript demonstrate that a vertebrate-specific interaction involving TFIID is essential for Sp1 activation of a TATA-less promoter. Although several models could explain this finding, an attractive hypothesis is that a specific interaction between Sp1 and human TFIID is non-functional with Drosophila TFIID. Since three different interactions between Sp1 and TFIID have been described (9,20-23), a defect in any one of the interactions could explain the results. An alternative hypothesis is that the Drosophila TFIID complex lacks a domain or subunit which carries out an essential interaction with another general transcription factor or which stabilizes the TFIID-DNA interaction during Sp1 activation from TATA-less promoters. According to the data the missing TFIID domain would be critical only during stimulation of TATA-less transcription by a specific class of activation domains. Furthermore, the interaction would not be essential for basal Inr recognition or function or for Inr function during Sp1 activation of a TATA-containing promoter.
We favor the latter of these two hypotheses because the Sp1 mutant analysis adds an additional level of complexity to the former hypothesis. The mutant analysis revealed that the Sp1 Bc and A domains are necessary for transcriptional activation in Drosophila. We previously showed that either of these domains is sufficient for activation of Inr-mediated transcription in human cells, when tested as GAL4 fusion proteins (10). Since these domains appear to function in Drosophila cells, they are unlikely to contribute to the species-specific defect. It is possible that these domains carry out two critical interactions, one of which cannot take place when Sp1 is expressed in Drosophila. However, because of the small size of the Bc domain it seems unlikely to carry out two essential interactions, leading us to favor the second hypothesis proposed above.
The component of human TFIID that contributes to the vertebrate-specific activity remains to been established. A small number of human TAFs have not been found in Drosophila (40) and must therefore be considered as candidates. However, any of the TFIID subunits may lack a critical domain or possess an evolutionarily diverged domain that cannot impart the essential activity. We also have not determined whether other components of the transcription machinery are involved in the essential species-specific function. To gain insight into this question in vitro transcription experiments with human TFIID added to Drosophila extracts must be performed. Unfortunately, Drosophila extracts do not support efficient activation by Sp1 or other activators, but rather support anti-repression (data not shown).
The results obtained in Drosophila cells with co-transfected Sp1 are interesting to compare with the results obtained in mammalian cells with GAL4-Sp1 fusion proteins (10). In the mammalian experiments the N-terminal glutamine-rich activation domains were found to selectively activate transcription from promoters containing an Inr element. Activation of promoters containing only a TATA box required fusion proteins with both the N-terminal and the C-terminal domains of Sp1 (10). Consistent with the mammalian studies, all of the Sp1 proteins which activated transcription from the TATA-only promoter in Drosophila cells contain both N-terminal and C-terminal domains. Interestingly, GAL4 fusion proteins containing only the glutamine-rich activation domains of Sp1 were inactive with any of the core promoters when expressed in Drosophila cells (data not shown). Although the reason for the inactivity was not explored in depth, the results are consistent with our expectations; the glutamine-rich domains appear to require an Inr to function but in Drosophila cells Sp1 activation through an Inr is defective.
The selective inability of Sp1 to activate TATA-less transcription is consistent with a previous study by Pugh and Tjian (16), who found that purified Drosophila TFIID could not support Sp1-activated transcription from a TATA-less promoter when added to a human in vitro transcription assay. That study compared partially purified human TFIID to highly purified Drosophila TFIID in an in vitro assay. Since only the human TFIID supported Inr-mediated transcription, the proposed explanation was that an essential protein present in partially purified human TFIID was lost during extensive purification of the Drosophila TFIID. The in vivo experiments shown here, combined with the in vitro experiments performed with highly purified human TFIID, strongly suggest that the deficiency observed in the previous study resulted from species specificity.
Although the results shown here are consistent with those described above (16), they are inconsistent with a recent study by Colgan and Manley (29), who reported that in Drosophila cells Sp1 activates an Inr-containing promoter even more strongly than a TATA-Inr promoter. In that study the transcription start sites were not determined because promoter activity was measured by an indirect CAT assay, rather than by direct RNA analysis. Since numerous AT-rich sequences are capable of functioning as TATA boxes (28,41,42), it remains possible that the promoter activity detected was mediated by AT-rich sequences within the vector rather than by the Inr element. Consistent with this hypothesis, we have had considerable difficulty studying Inr activity using indirect reporter assays and have found that the reporter activities routinely differ from the specific reporter mRNA levels (data not shown). Another finding which might explain the CAT assay results (29) is that the Sp1-Inr-CAT plasmids used in the previous study contain a sequence downstream of the Inr that exhibits homology to the DPE reported by Burke and Kadonaga (34). The presence of a DPE might facilitate Sp1 stimulation through an Inr in Drosophila cells and might explain why the Inr promoter was stronger than the TATA-Inr promoter in those studies (29).
When ectopically expressed in Saccharomyces cerevisiae Sp1 possesses no transcriptional activation function (43), whereas in mammalian cells Sp1 activates all relevant promoters. It therefore might not be surprising that in Drosophila some but not all of the Sp1 activation properties are functional. Clearly, this result does not suggest that the Drosophila genome lacks TATA-less promoters, as numerous examples have been reported. Moreover, Figure 1D shows that a specific activation domain from the Drosophila ftz gene is capable of activating transcription from TATA-less promoters in Drosophila. Instead, the results suggest that the types of domains capable of activating transcription in Drosophila cells from promoters that lack a TATA box are more limited than the domains used for TATA-less transcription in mammalian cells. An understanding of the mechanistic basis of this vertebrate-specific activity will provide insight into the mechanism of transcription activation in general and the mechanism of activation from TATA-less promoters in particular.
We are grateful to J.T.Kadonaga, in whose laboratory the Drosophila TFIID was purified, and to D.Black, for critical reading of the manuscript. We also thank A.Courey, G.Gill, J.Manley, E.Pascal, R.Tjian and A.Winoto for providing expression plasmids and A.Courey for providing nuclear extracts from Drosophila embryos. This work was supported by the Howard Hughes Medical Institute (S.T.S.) and by NIH grant GM41249 (to J.T.Kadonaga).
Nucleic Acids Research
Pages
Introduction
Materials And Methods
Plasmids
Transient transfections
In vitro transcription
Results
Sp1 cannot efficiently activate transcription in Drosophila cells from an Inr-containing promoter
The TdT Inr functions in Drosophila cells
Transcriptional activation by Sp1 in Drosophila cells requires a strong TATA box
Functional domains of Sp1 required for activation of TATA and TATA-Inr promoters
TFIID contributes to the species specificity of Sp1 activation
Discussion
Acknowledgements
References
REFERENCES
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