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Genetics, Vol. 167, 1275-1280, July 2004, Copyright © 2004
doi:10.1534/genetics.104.027037

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The Mod(mdg4) Component of the Su(Hw) Insulator Inserted in the P Transposon Can Repress Its Mobility in Drosophila melanogaster

Marina Karakozova, Ekaterina Savitskaya, Larisa Melnikova, Aleksandr Parshikov and Pavel Georgiev1

Department of the Control of Genetic Processes, Institute of Gene Biology, Russian Academy of Sciences, Moscow 119334, Russia

1 Corresponding author: Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilov St., Moscow 119334, Russia.
E-mail: georgiev_p{at}mail.ru

Manuscript received February 1, 2004. Accepted for publication April 8, 2004.


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 LITERATURE CITED
 
Transposable element P of Drosophila melanogaster is one of the best-characterized eukaryotic transposons. Successful transposition requires the interaction between transposase complexes at both termini of the P element. Here we found that insertion of one or two copies of the Su(Hw) insulator in the P transposon reduces the frequency of its transposition. Inactivation of a Mod(mdg4) component of the Su(Hw) insulator suppresses the insulator effect. Thus, the Su(Hw) insulator can modulate interactions between transposase complexes bound to the ends of the P transposon in germ cells.

"INSULATORS" is the name given to a class of DNA sequence elements that have properties consistent with a role in limiting enhancer activity (GEYER and CLARK 2002; WEST et al. 2002). In Drosophila, there is a well-characterized insulator within the 5'-untranslated region of the gypsy retrotransposon (HOLDRIDGE and DORSETT 1991; GEYER AND CORCES 1992; ROSEMAN et al. 1993; CAI and LEVINE 1995, 1997). The gypsy insulator consists of reiterated binding sites for the Su(Hw) protein (SPANA et al. 1988; MAZO et al. 1989). Genetic and molecular approaches have been used to identify and characterize two protein components of the Su(Hw) insulator. One of them, encoded by the suppressor of Hairy wing [su(Hw)] gene, is a zinc-finger protein that binds to insulator DNA (DORSETT 1990; SPANA and CORCES 1990). Modifier of mdg4 [Mod(mdg4)] is the second protein component of the gypsy insulator complex (GERASIMOVA et al. 1995; GEORGIEV and KOZYCINA 1996). The mod(mdg4) gene, also known as E(var)3-93D, encodes a large set of individual protein isoforms with specific functions in regulating the chromatin structure of different genes (GERASIMOVA et al. 1995; BUCHNER et al. 2000). Biochemical studies with purified Su(Hw) and Mod(mdg4) proteins indicate that one isoform, Mod(mdg4)-67.2, interacts with the enhancer-blocking domain of the Su(Hw) protein (GAUSE et al. 2001; GHOSH et al. 2001). All Mod(mdg4) isoforms share an amino-terminal 402-residue domain that includes a BTB/POZ motif (GERASIMOVA et al. 1995; BUCHNER et al. 2000). It was shown (GAUSE et al. 2001; GHOSH et al. 2001) that the BTB domain of Mod(mdg4)-67.2 is involved in self-interactions, whereas the C-terminal region of the protein is involved in interactions with the Su(Hw) protein. The interaction between BTB domains of Mod(mdg4) is postulated to be important for the insulator function (GAUSE et al. 2001; GHOSH et al. 2001). The homozygously viable mod(mdg4)u1 mutation is a Stalker transposon insertion into the "C-terminal" exon unique to the Mod(mdg4)-67.2 mRNA (GERASIMOVA et al. 1995; BUCHNER et al. 2000). Similarly to mod(mdg4)u1, the mod(mdg4)T6 allele is homozygously viable and produces a Mod(mdg4)-67.2 protein truncated short of the C terminus (MONGELARD et al. 2002). The truncated versions of the Mod(mdg4)-67.2 protein produced by either mutation do not interact with Su(Hw) (GAUSE et al. 2001; GHOSH et al. 2001).

The prevalent structural model suggests that boundary elements or insulators subdivide eukaryotic chromosomes into functionally and structurally autonomous domains (GERASIMOVA and CORCES 2001; GEYER and CLARK 2002; WEST et al. 2002; KUHN and GEYER 2003). The insulators determine the limits of higher-order "looped" chromatin domains by interacting with each other or/and with some other nuclear structure. Consistent with the idea that pairing between Su(Hw) insulators is responsible for the boundary activity, duplication of the Su(Hw) insulator neutralized the enhancer-blocking activity and even strengthened activation by the enhancer (CAI and SHEN 2001; MURAVYOVA et al. 2001). At the same time, two Su(Hw) insulators flanking either the enhancer or the promoter are still capable of blocking enhancer-promoter communication. These results suggest that interaction between the Su(Hw) insulators may facilitate activation by bringing regulatory elements together or block the interaction between them. The main prediction of this model is that pairing between insulators can block interactions between all kinds of proteins.

Here we examined whether insertion of one or two copies of the Su(Hw) insulator in the P transposon would suppress the frequency of transposition, which depends on the efficiency of interaction between transposase complexes bound to P ends. Full-length P elements are 2.9 kb and encode an 87-kD transposase protein (O'HARE and RUBIN 1983). P-element transposition requires ~150 bp of sequence at each end of the P element (KAUFMAN et al. 1989). These sequences include 31-bp terminal inverted repeats, internal transposase-binding sites, and internal 11-bp inverted repeats (KAUFMAN et al. 1989; MULLINS et al. 1989). During P-element transposition, transposase catalyzes the cleavage and strand-transfer steps of the transposition reaction (KAUFMAN and RIO 1992; BEALL and RIO 1997). The P-element transposase requires both 5' and 3' termini of the P element for efficient DNA cleavage, suggesting that a synaptic complex forms on the P-element termini prior to cleavage (BEALL and RIO 1997, 1998). Insertion of one or two copies of the Su(Hw) insulator in the P transposon considerably diminishes the frequency of its transpositions. We suggest that the Su(Hw) insulator can interfere with proper interaction between the protein complexes involved in the P transposition.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 LITERATURE CITED
 
Drosophila strains, transformation, and genetic crosses:
All flies were maintained at 25° on a standard yeast medium. The line bearing the mod(mdg4)T6 mutation in the mod(mdg4) gene was obtained from D. Dorsett. The structure and origin of the mod(mdg4)u1 and mod(mdg4)T6 mutations are described by GERASIMOVA et al. (1995) and MONGELARD et al. (2002). All other mutant alleles and chromosomes used in this work and all balancer chromosomes are described in LINDSLEY and ZIMM (1992).The transposon constructs, together with a transposase source, P25.7wc (KARES and RUBIN 1984), were injected into y– ac– w1118 preblastoderm embryos. Transformed lines [y– ac– w1118 P(y+; w+)] carrying a transposon insertion at the X chromosome were examined by Southern blot hybridization to check for transposon integrity and copy number. Lines with the homozygous mod(mdg4)u1 or mod(mdg4)T6 mutation were obtained as described in GEORGIEV and KOZYCINA (1996). The lines with Su(Hw) excisions were obtained by crossing the flies bearing the transposons with the line ywi; Cyo, P[w+,cre]/Sco expressing Cre recombinase (SIEGAL and HARTL 2000). All excisions were confirmed by PCR analysis.

As the source of P transposase (ROBERTSON et al. 1988), we used the w1, P[ry+{Delta}2-3](99B), Sb e/TM1, e strain. The transposase gene P[ry+{Delta}2-3](99B) was abbreviated as {Delta}2-3. The frequency of transposition from the X chromosome to autosomes was examined in the F1 progeny of y– ac– w1118 P(y+; w+); {Delta}2-3 Sb/+ males individually crossed to five to six y w/y w or y1u1 scD1 w/y1u1 scD1 w females. The frequencies of transposition were calculated as the number of y w/Y; P(y+; w+) or y1u1 scD1 w/Y; P(y+; w+) males (with pigmented eyes and cuticle) divided by the total number of scored y w/Y or y1u1 scD1 w/Y males (with yellow cuticle and white eyes). The frequencies of nondisjunction [appearance of y– ac– w1118 P(y+; w+) males in the F1 progeny] were in the range of 3–12%.The y2 scD1 w; P[ry+{Delta}2-3](99B) mod(mdg4)u1 Sb/TM6 line was constructed to examine the P transpositions on the mod(mdg4)u1 background. The frequency of transpositions on the mod(mdg4)u1 background was examined in the progeny of y– ac– w1118 P(y+; w+); {Delta}2-3 Sb mod(mdg4)u1/mod(mdg4)u1 males individually crossed to five to six y w/y w or y1u1 scD1 w/y1u1 scD1 w females.

The dominant effect of the mod(mdg4)u1 mutation was examined in the progeny of the cross of y– ac– w1118 P(y+; w+); {Delta}2-3 Sb mod(mdg4)u1/mod(mdg4)+ males with y w females. The frequency of transposition in the mod(mdg4)u1/mod(mdg4)T6 trans-heterozygote was examined in the progeny of y– ac– w1118 P(y+; w+); {Delta}2-3 Sb mod(mdg4)u1/mod(mdg4)T6 males crossed to y w females. Details of the crosses used for genetic analysis and for excision of the Su(Hw) insulator are available upon request.

Transgenic constructs:
The ESY and ES(–893)YSW transgenic lines were obtained previously and described in MURAVYOVA et al. (2001). The WS transgenic lines were obtained from A. Golovnin.

The 8-kb fragment containing the yellow gene was kindly provided by P. Geyer. The 3-kb SalI-BamHI fragment containing the yellow regulatory region (yr) was subcloned into BamHI + XhoI-digested pGEM7 (yr plasmid). The 5-kb BamHI-BglII fragment containing the coding region (yc) was subcloned into CaSpeR3 (C3-yc). The yellow regulatory region with the Su(Hw) inserted at –893 bp (yr-su) was described in MURAVYOVA et al. (2001).

The 430-bp gypsy sequence containing the Su(Hw)-binding region was PCR amplified from the gypsy retrotransposon. After sequencing to confirm its identity, the product was inserted between two loxP sites [lox(su)]. The lox(su) fragment was blunt ligated into a CaSpeR2 vector treated with BglII [C2-lox(su)]. The 5-kb BamHI-BglII fragment containing the coding region (yc) was subcloned into CaSpeR2-lox(su), (C2-lox(su)-yc, or CaSpeR3 (C3-yc). The modified Caspew15 vector (Caspew15-su) containing the Su(Hw) insertion from the 3' side of the mini-white gene was obtained from A. Golovnin.

For (S)WS, the lox(su) fragment was ligated into Caspew15-su treated with XbaI; for ESY(S)W, the yr-su fragment was ligated into C2-lox(su)-yc treated with XbaI and BamHI; and for E(S)YW, the lox(su) fragment was ligated into yr treated with Eco47III at position –893 [yr-lox(su)]. The yr-lox(su) fragment was ligated into C3-yc treated with XbaI and BamHI. For EY(S)W, the yr fragment was ligated into C2-lox(su)-yc treated with XbaI and BamHI.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 LITERATURE CITED
 
Insertion of one or two copies of the Su(Hw) insulator in the P transposon suppresses the frequency of transposition:
In the first series of experiments, we used previously described transgenic lines carrying P transposons with the yellow and white marker genes or with only the white gene (Figure 1). The yellow gene is required for dark pigmentation of Drosophila larval and adult cuticle and its derivatives, while the white gene is required for eye pigmentation. In the ESY construct, the Su(Hw) insulator was inserted at –893 bp relative to the yellow transcription start site. In the ES(–893)YS construct, the yellow gene is flanked by the Su(Hw) insulators, one at position –893 and the other downstream of the yellow gene. The WS has an insertion of the Su(Hw) insulator from the 3' end of the white gene. The P element was mobilized in three ESY, four ES(–893)YS, and two WS lines, which had the transposon insertion on the X chromosome. As a result (Table 1), we found that in seven tested transgenic lines carrying both yellow and white genes, the frequency of P transposition from the X chromosome to autosomes was in the range of 0.8–1.3%. Two transgenic lines with the WS transposon, containing only sequences of the white gene, had even lower transposition frequencies: 0.05 and 0.4%.



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  		FIGURE 1.— Transposon constructs used to test the suppression of P transpositions. The maps of the constructs (not drawn to scale) show the yellow wing and body enhancers (En-w and En-b, respectively) as open boxes. The Su(Hw) insulator is shown as a solid box, and the yellow and white genes as open boxes with arrows indicating the direction of transcription. The thick arrows marked LOX represent the target sites of the Cre recombinase.

 

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  		TABLE 1 Role of Mod(mdg4) in repression of transposition of the P constructs containing one or two copies of the Su(Hw) insulator

 
As Mod(mdg4)-67.2 is an important component of the Su(Hw) insulator, we examined the frequency of transposition on the mod(mdg4)u1 mutant background that produces a nonfunctional version of the Mod(mdg4)-67.2 protein. On the mod(mdg4)u1 background, the transposition frequency was elevated 3- to 7-fold in most of the transgenic lines (Table 1). The striking effect of the mod(mdg4)u1 mutation was found in the case of the WS(1) transgenic line (Table 1), which showed a 100-fold increase in the P transpositions on the mod(mdg4)u1 background. The results obtained suggest that the presence of one or two copies of Su(Hw) in transposons reduces the frequency of transposition, while inactivation of the Mod(mdg4) component of the Su(Hw) insulator reactivates transpositions.

Mod(mdg4)-67.2 is essential for suppression of P transpositions by the Su(Hw) insulator:
To find out if other components of the Su(Hw) insulator in addition to Mod(mdg4) are required for blocking the transpositions, we compared the frequency of transposition of the P transposon inserted at the same site before and after deletion of the Su(Hw) insulator. The Su(Hw) insulator was flanked by Cre recognition target (LOX) sites to permit its excision from transgenic flies by crossing the latter with flies expressing Cre recombinase (SIEGAL and HARTL 2000). The Su(Hw) insulator flanked by LOX sites was inserted either at –893 bp, E(S)YW, or between the yellow and white genes, EY(S)W (Figure 1). Three EY(S)W and three E(S)YW transgenic lines that contain a single P transposon on the X chromosome were established. The frequency of transposition was examined in these transgenic lines and their derivatives were generated by deletion of Su(Hw) on the wild-type or the mod(mdg4)u1 mutant background (Table 2). Deletion of the Su(Hw) insulator significantly increased the frequency of transposition only in the former case. The inability of the mod(mdg4)u1 mutation to affect P transpositions when the Su(Hw) insulator has been deleted confirms that Mod(mdg4)-67.2 operates by interacting with the Su(Hw) insulator. The quite similar levels of P transposition on the mod(mdg4)u1 background and after deletion of the Su(Hw) insulator suggest that mainly the Mod(mdg4)-67.2 component of the Su(Hw) insulator is required for suppression of P transposition.


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  		TABLE 2 Correlation between the frequency of transposition and the number of copies of the Su(Hw) insulator in the P constructs

 
As the mod(mdg4)u1 mutation was obtained in a highly mutable line (GEORGIEV and GERASIMOVA 1989), it is possible that, in addition to mod(mdg4)u1, another mutation that is responsible for the repression of the P transpositions has arisen. To eliminate the role of genetic background, we first examined the frequency of P transposition in three E(S)YW transgenic lines on the mod(mdg4)u1/mod(mdg4)+ background. The comparably low frequency of P transposition on the wild-type and the mod(mdg4)u1/mod(mdg4)+ backgrounds suggests that the effect of mod(mdg4)u1 is recessive (Table 2). Next, we examined P transpositions in the same transgenic lines on the mod(mdg4)T6/mod(mdg4)u1 background, where mod(mdg4)T6 produced a truncated version of the Mod(mdg4)-67.2 protein similar to that produced by the mod(mdg4)u1 mutation (MONGELARD et al. 2002). The mod(mdg4)T6/mod(mdg4)u1 trans-heterozygote restored transpositions in E(S)YW transgenic lines similar to those restored by the mod(mdg4)u1 homozygotes (Table 2). Because mod(mdg4)u1 and mod(mdg4)T6 have different origins (GERASIMOVA et al. 1995), we conclude that inactivation of Mod(mdg4) rather than another unidentified mutation in the mod(mdg4)u1 line is responsible for the effect of the mod(mdg4)u1 mutation.

The pairing between two Su(Hw) insulators does not neutralize the repression of transpositions:
We initially observed (Table 1) that insertion of one or two copies of the Su(Hw) insulator into the P transposon had a similar effect on its transpositions. As pairing between two Su(Hw) insulators neutralizes each other's enhancer-blocking activity (GAUSE et al. 1998; CAI AND SHEN 2001; MURAVYOVA et al. 2001; MELNIKOVA et al. 2002; KUHN et al. 2003), it is possible to explain the lack of significant difference in the transposition frequency between transposons with either one or two Su(Hw) insulators by location of the ESY and ES(–893)YS insertions in different regions of the X chromosome.

To further examine whether the pairing between the Su(Hw) insulators can inhibit the repression of P transpositions, one of the Su(Hw) insulators in the (S)WS and ESY(S)W constructs was flanked by LOX sites (Figure 1). Two (S)WS and three ESY(S)W transgenic lines bearing a single transposon insertion at the X chromosome were examined before and after excision of the Su(Hw) insulator (Table 2). In only one [(S)WS (2)] line, the frequency of transposition was significantly reduced after deletion of the Su(Hw) insulator. In four other transgenic lines, the frequency of transposition was approximately the same for transposons with one and two copies of the Su(Hw) insulator. As in the previous experiments, the frequency of P transposition was markedly elevated on the mod(mdg4)u1 mutant background, confirming that the Su(Hw) insulator is responsible for the repression of transpositions in all transgenic lines tested. Thus, the pairing between two Su(Hw) insulators inserted between the ends of the P transposon does not appreciably neutralize the blocking of its transposition.


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 LITERATURE CITED
 
The results obtained show that the Su(Hw) insulator affects the P transpositions in germ cells. It is most likely that the Su(Hw) insulator interferes with the interaction between protein complexes bound to the ends of the P transposon. Previous studies have shown that the loss of Mod(mdg4)-67.2 attenuates enhancer blocking by the Su(Hw) insulator at some genes but not at others (GEYER and CLARK 2002; KUHN and GEYER 2003). In several cases, the absence of Mod(mdg4)-67.2 converts the Su(Hw) insulator into a repressor (GEORGIEV and KOZYCINA 1996; CAI and LEVINE 1997; WEI and BRENNAN 2001). These data suggest that the Mod(mdg4)-67.2 isoform is involved in only some Su(Hw) insulator functions. In contrast, Mod(mdg4)-67.2 fulfills the main role in the repression of P transpositions. According to the accepted structural models (GERASIMOVA and CORCES 2001; WEST et al. 2002), the putative interaction between BTB domains of Mod(mdg4)-67.2 is required for generation by the Su(Hw) insulators of looped chromatin domains that preclude interactions between regulatory elements residing in distinct domains. From this viewpoint, a plausible explanation of the inability of paired, closely spaced Su(Hw) insulators to block enhancer-promoter communication is that they would preferentially interact with each other. This local interaction precludes the paired Su(Hw) insulators from interacting with other Su(Hw) insulators, which is necessary to separate the enhancer from the promoter.

Here we show that, in contrast to the neutralization of the enhancer blocking, pairing between two Su(Hw) insulators located between the ends of the P transposon does not significantly neutralize the repression of P transpositions. Thus, it is most likely that Mod(mdg4)-67.2 directly blocks the interaction between protein complexes bound to the ends of the P element. As shown for the BTB-containing PZLF and Bcl6 proteins, a charge pocket, formed by apposition of the two monomers, represents a molecular structure involved in recruitment of transcriptional repression complexes (MELNICK et al. 2002). It is possible that the Mod(mdg4)-67.2 dimers either directly interact with transposase complexes or recruit other proteins that interfere with the formation of the transposase complexes at the ends of the P transposon. Alternatively, Mod(mdg4)-67.2 might interact with proteins bound to the promoter region of the P transposon. Since the transposase binds to the site overlapping the promoter (KAUFMAN et al. 1989; MULLINS et al. 1989), the assumed interaction between the promoter complex and Mod(mdg4)-67.2 might interfere with the transposase binding to the P transposon. Further molecular study is required for understanding the molecular basis of the described phenomenon.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
LITERATURE CITED
 
We thank A. V. Galkin for a critical reading and correction of the manuscript. This work was supported by the Russian Academy of Science Program, Molecular and Cellular Biology, and by an International Research Scholar award from the Howard Hughes Medical Institute to P.G. The work of E.S. was also supported by a stipend from the Center for Medical Studies, University of Oslo.


   LITERATURE CITED
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 LITERATURE CITED
 

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