Oocyte and Embryo

trl is expressed in the germarium were it is found in the nuclei of stem cells, cystoblasts and the 2-16 cell cysts. Protein is detected in nurse cells and the oocyte as well as follicule cells of vitellogenic egg chambers (Bhat, 1996).

Prominent TRL protein is found in the syncytial blastoderm stage and persists throughout most of embryonic development with no apparent spatial regulation, indicating that TRL is a ubiquitous factor (Soeller, 1993).

The GAGA factor of Drosophila encoded by the Trithorax-like gene is known to maintain expression of many Drosophila genes including homeotic ones, through configuration remodeling of local chromatin. The complicated transcript pattern of Trl gene has been examined at all stages of development. The study of Trithorax-like gene expression in whole flies and in the brains and salivary glands of third instar larvae, including adjacent imaginal discs, show tissue-specific variations in transcript patterns and dependence of these patterns on the temperature of development (14-37 degrees C). Trl generates various tissue-specific transcripts: in larvae developed at 18-30 degrees C, only one (2.0 kbp) transcript is observed in salivary glands, yet three (1.8, 2.0 and 2.5 kbp) are observed in brain and the adjacent imaginal discs. The transcriptional activity of the gene depends on temperature. In salivary glands of larvae, two additional transcripts occur at 14 degrees C that are never found at normal temperatures (18-30 degrees C). Of the three transcripts observed at normal temperatures, only the 2.5 Kb transcript occurs at 14 decrees in the brain and imaginal discs. Position effect variegation is known to be enhanced at low temperatures, but a connection between the temperature-dependent changing TRL transcript pattern and the enhancement of PEV has yet to be studied. All transcripts except for the one 2.0 kb in length disappear in flies grown at 37 degress C. This is interesting in light of the fact that Trl has been reported to exert regulation upon the activation of heat shock genes (Baricheva, 1997).

The heterochromatic binding of GAGA factor and Proliferation disrupter (Prod) proteins were examined during the cell cycle in Drosophila melanogaster and sibling species. Prod protein is a putative gene regulator thought to bind to a different satellite repeat than does GAGA factor. Like GAGA factor, Prod labels ~400 euchromatic sites, but is excluded from the chromocenter in polytene chromosomes, and shows a restricted pattern of heterochromatin binding at metaphase. It is thought that the sites of anti-Prod binding correspond to locations of (AATAACATAG)n satellite repeats in D. melanogaster. GAGA factor binding to the brownDominant AG-rich satellite sequence insertion is seen at metaphase; however, no binding of GAGA factor to AG-rich sequences is observed at interphase in polytene or diploid nuclei. Comparable mitosis-specific binding was found for Prod protein to its target satellite in pericentric heterochromatin. At interphase, these proteins bind numerous dispersed sites in euchromatin, indicating that they move from euchromatin to heterochromatin and back every cell cycle. The presence of Prod in heterochromatin for a longer portion of the cell cycle than GAGA factor suggests that they cycle between euchromatin and heterochromatin independently. It is proposed that movement of GAGA factor and Prod from high affinity sites in euchromatin occurs upon condensation of metaphase chromosomes. Upon decondensation, GAGA factor and Prod shift, as a self-assembly process, from low affinity sites within satellite DNA back to euchromatic sites (Platero, 1998).

Effects of Mutation or Deletion

Trithorax-like appears to have a global role in chromosome structure and function. There are a spectrum of nuclear cleavage cycle defects observed in mutant embryos. These defects include asynchrony in the cleavage cycles, failure in chromosome condensation, abnormal chromosome segregation and chromosome fragmentation. These defects are likely to be related to the association of the TRL protein with heterochromatic satellite sequences observed throughout the cell cycle (Bhat, 1996)

Flies doubly heterozygous for GAGA and Ubx exhibit larger halteres than flies mutant for Ubx alone, and, with incomplete penetrance and variable expressivity, show homeotic transformations of the haltere and postnotum into wing. When zeste mutations are crossed into this double heterozygotic background, a similar range of phenotypes is observed. However, the fraction of animals displaying the enhanced Ubx phenotype is increased 2 to 19 fold, depending on the GAGA allele used. This increase in penetrance is observed with two different zeste alleles. Therefore, mutations in zeste increase the likelihood that limiting amouts of GAGA factor and UBX will lead to reduced expression of Ubx and to homeotic transformation of haltere into wing (Laney, 1996).

The glutamine-rich region of GAGA protein is responsible for the formation of fibers in vitro which, on the basis of their tinctorial properties and CD spectra, may be classified as amyloid fibers. A large structural change, probably resulting in beta-sheet structure, is observed upon fiber formation. Mutants containing the central region, either alone or together with the glutamine-rich region, are largely lacking in secondary structure but they bind specifically to the cognate DNA and are able to remodel chromatin in vitro. Consequently, neither the N-terminal domain nor the C-terminal glutamine-rich regions of the GAGA factor are necessary for chromatin remodeling in vitro (Agianian, 1999).

GAGA factor is required for dosage compensation in males and for the formation of the male-specific-lethal complex chromatin entry site at 12DE

Drosophila males have one X chromosome, while females have two. To compensate for the resulting disparity in X-linked gene expression between the two sexes, most genes from the male X chromosome are hyperactivated by a special dosage compensation system. Dosage compensation is achieved by a complex of at least six proteins and two noncoding RNAs that specifically associate with the male X. A central question deals with how the X chromosome is recognized. According to a current model, complexes initially assemble at ~35 chromatin entry sites on the X and then spread bidirectionally along the chromosome where they occupy hundreds of sites. This study shows that mutations in Trithorax-like (Trl) lead to the loss of a single chromatin entry site on the X at 12DE, male lethality, and mislocalization of dosage compensation complexes (Greenberg, 2004).

Assembly of the dosage compensation complex depends most critically upon Msl1 and Msl2 and these two MSL proteins may provide some type of scaffold for recruiting/stabilizing other components of the complex. These other components include the two noncoding RNAs, roX1 and roX2, which have been implicated in targeting the complex to entry sites on the X chromosome. In addition, the chromatin-modifying enzymes themselves, Mof-1, a histone acetylase, and JIL-1, a tandem histone kinase, the putative helicase, Mle, and the Msl3 protein, are believed to associate with the complex through specific interactions. All but one of these factors appears to function primarily, if not exclusively, in the MSL dosage compensation system. The exception is the JIL-1 kinase that is required not only for proper dosage compensation, but also for other aspects of transcriptional regulation that are vital to both sexes. It would be reasonable to anticipate that other factors like JIL-1 that have crucial activities in dosage compensation, while at the same time functioning in other processes that are important for both sexes, will be identified. This seems to be true for the GAGA factor that is encoded by the Trl gene (Greenberg, 2004).

The importance of the GAGA factor in many aspects of gene regulation and chromatin dynamics has been extensively documented. Evidence presented in this study indicates that GAGA also has a more specialized role in X chromosome dosage compensation. (1) Heteroallelic combinations of weak and strong Trl mutations have much greater effects on male than on female viability. In fact, the differences in the viability of the sexes in the two heteroallelic Trl mutant combinations tested in this study are equivalent to, if not more pronounced than, those reported for mutations in jil-1. (2) As might be expected if the functioning of the dosage compensation system is compromised when Trl function is impaired, the male lethal effects of the two heteroallelic Trl mutant combinations are found to be exacerbated by reductions in the dose of either msl1 or msl2. Moreover, although the hypomorphic Trl13C allele by itself exhibits no sex-specific lethality when homozygous, male-specific lethality can be induced by reducing the dose of the MSL complex. Conversely, increasing the level of the Msl2 gene product using an hsp83 promoter to drive the expression of an msl2 cDNA partially rescues males carrying Trl mutations (Greenberg, 2004).

Although Trl appears to function primarily in chromatin remodeling rather than as a dedicated component of the transcriptional machinery, it is involved in the expression of a very large and diverse array of genes. Since males must upregulate transcription of X-linked genes to achieve the same level of expression as females, it would be reasonable to suppose that males are likely to be much more dependent upon the proper functioning of the general transcriptional machinery than are females. Accordingly, any reduction in the activity of a factor critical for transcription would be expected to have considerably more deleterious effects on males than on females. If this idea is correct, then the male-specific lethality of Trl mutations could simply be due to a decline in the overall activity or efficiency of the transcriptional machinery rather than to an effect specific to the process of dosage compensation itself. This 'impaired transcription' model would also explain why the male-specific lethal effects of Trl mutations are enhanced by a reduction in the dose of the msl genes and suppressed by increasing the dose of Msl2. Of course, this model predicts that hypomorphic mutations in components of the transcriptional apparatus should also exhibit male-specific lethality like mutations in Trl. Although some alleles of TAF250 do cause preferential male lethality, there is no evidence that compromising the activity of other general transcription factors affects males more than females. In fact, none of the many hypomorphic mutations in the gene coding for the 140-kD subunit of RNA polymerase II give rise to male lethality, and neither do mutations in the small subunit of TFIIA. An additional problem with the 'impaired transcription' model is that it would not account for the finding that Trl mutations enhance the female lethal effects of the hsp83:msl2 transgene. The opposite result would be expected, namely that Trl mutations would suppress the female lethal effects of ectopic Msl2 protein (Greenberg, 2004).

An alternative, more plausible explanation for the effects of Trl mutations on male viability is that the GAGA factor plays some important role in the functioning or activity of the msl-dependent dosage compensation system. In addition to accounting for both the male-specific lethality of Trl mutations and the genetic interactions between Trl and msl-complex genes, this suggestion would help explain two other findings. (1) Abnormalities in the distribution of the MSL complexes are observed in polytene chromosomes from Trl mutant males. These abnormalities include the presence of at least one ectopic site on the X chromosome and an increase in the number of autosomal sites. This redistribution of MSL complexes argues that the GAGA factor is important for correctly targeting the dosage compensation machinery to the X chromosome. A similar although more dramatic MSL redistribution is when roX1 and roX2 are simultaneously deleted in males. (2) One of the ~35 chromatin entry sites on the X chromosome, at 12DE, is found to be missing in Trl mutants. Unlike any of the other chromatin entry sites observed in polytene chromosomes, GAGA is localized to the 12DE site. This finding argues that the GAGA factor is important in the formation/maintenance of this particular chromatin entry site. Neither of these effects on the chromosomal association of MSL complexes would be explained by a model in which the male-specific lethality of Trl mutations is due to some general reduction in the activity of the transcriptional machinery (Greenberg, 2004).

While it would be reasonable to propose that there is a direct connection between the defects in the chromosomal association of Msl complexes and male lethality, the precise mechanism is not entirely clear. One possibility is that male lethality is due to the loss of the 12DE entry site. Supporting this idea, MSL complexes formed at ectopic entry sites on the autosomes usually spread only limited distances. This also appears to be true on the X chromosome. It is thus possible that the two entry sites flanking 12DE, at 12C and 12F, would be unable to compensate completely for the loss of the 12DE site. As a consequence, insufficient levels of the MSL complex would be recruited into the 12C-12F interval in Trl mutant males to fully upregulate gene expression, and this might result in male lethality (Greenberg, 2004).

Although the loss of the 12DE entry might significantly impair the upregulation of genes in the 12C-F interval, there are at least two potential complications with this simple model. (1) It seems unlikely that a reduction in the level of expression of genes in the 12C-F interval would in itself be sufficient to cause male lethality. Unless this chromosomal interval contains genes specifically required for male viability (e.g., encoding components of the dosage compensation machinery), this model would predict that this same interval is haplo-insufficient in females. However, there is no indication that deletions in this chromosomal interval have significant effects on female viability. (2) While the 12DE entry site is absent (in Trl; msl3 mutants), no obvious perturbation is seen in the distribution of MSL complexes in this region of the X chromosome in Trl mutants that are wild type for the MSL genes. One explanation for this discrepancy is that defects in MSL-complex distribution in the vicinity of the 12DE site are obscured because the recruitment and spreading of complexes is much more robust in polytene chromosomes (which consist of hundreds of chromosomes whose sequences are aligned in precise register) than in chromosomes from polyploid or diploid nuclei. In fact, in polytene chromosomes MSL complexes can spread from ectopic entry sites on the autosomes not only in cis but also in trans and can even skip over large chromosomal segments (Greenberg, 2004).

This simple model would also not explain why MSL complexes in polytenes of Trl mutants localize to many ectopic sites on the autosomes. The presence of these autosomal complexes indicates that there must be some defect in the loading of complexes onto the X chromosome. Since no obvious reduction is seen in the amount of complex in the 12C-F interval, it seems unlikely that the loss of the 12DE entry site alone could account for the presence of the autosomal complexes. Instead, this would suggest that the GAGA factor may be important in the loading or spreading of complexes from a number of entry sites located elsewhere on the X in addition to the 12DE entry site. In this respect, it is notable that the GAGA factor binds in close proximity to five MSL-complex entry sites, including roX1. If GAGA is important in the loading or spreading of complexes from a number of 'Trl-dependent' entry sites in addition to 12DE, the male lethal effects of the Trl would be explained by the cumulative effects of a reduction in the expression of genes located in several different chromosomal regions rather than in just the 12C-F interval (Greenberg, 2004).

If loss of GAGA binding reduces the activity of only a subset of the chromatin entry sites, it would be expected that dosage compensation would be compromised over some parts of the X chromosome, but not others. This would help to explain why the weak female lethal effects of the H83M2 transgene at 22° are greatly enhanced in Trl mutants. Under conditions in which Msl2 protein expression is limiting, defects in the spreading of MSL complexes from Trl-dependent entry sites could lead to a more efficient loading and subsequent spreading from sites that are independent of Trl function. Female lethality would be induced because of the increased concentration of complexes in regions served by 'Trl-independent' entry sites. A hint that this may happen comes from the study that found that elimination of one or the other of the roX chromatin entry sites results in a redistribution of the overexpressed Msl1 and Msl2 proteins to the other parts of the X chromosome (Greenberg, 2004).

Finally, it is important to note that the effects on MSL-complex distribution seen in salivary gland polytene chromosomes are unlikely to reproduce the defects in nonpolytene tissues that most directly contribute to male lethality. (1) The available evidence suggests that GAGA interacts with different sites in different tissues. Hence, it is possible that the GAGA factor may be important for the formation or maintenance of entry sites in addition to 12DE in other cell types. (2) Because of a substantial maternal contribution, homozygous null Trl alleles are not lethal until larval stages, while the lethal phase of the hypomorphic mutant combinations used in the studies reported here is even later, during the pupal stage. It is likely that lethality occurs when the level of the GAGA factor becomes sufficiently depleted by successive rounds of cell division that it drops below a critical threshold in cells that are essential for viability. Since polytenized cells stop dividing, the level of GAGA factor may remain high enough in these cells to keep the functioning of the dosage compensation system from being seriously impaired. (3) GAGA is known to bind to one of the major satellite sequences in centromeric heterochromatin. Since centromeric heterochromatin is underreplicated in polytenized chromosomes, the effective concentration of the noneuchromatic GAGA-binding sites in salivary gland cells will be much less than that in cells that do not have polytenized chromosomes. This would mean that, under conditions of limiting GAGA factor, more should be available to associate with the euchromatic regions of X chromosome salivary gland cells than in cells with diploid nuclei (Greenberg, 2004).

An important question is how the GAGA factor functions in the formation and/or maintenance of the 12DE entry site. Given its role in generating nucleosome-free regions of chromatin, a plausible idea is that GAGA is required to ensure that the 12DE site is readily accessible to appropriate components of the MSL complex. In Trl mutants, the 12DE entry site and/or the immediately surrounding DNA would be packaged into a nucleosomal structure that cannot be used to initiate MSL-complex assembly, is refractory to the assembly of stable complexes, or is not compatible with the spreading of the complex in cis. The idea that a nucleosome-free region of chromatin is critical for entry site function is supported by recent studies on the roX1 entry site. A small ~200-bp sequence within the roX1 genes can direct the assembly of MSL complexes at ectopic sites and this sequence is hypersensitive to nuclease digestion in male but not female chromatin. Further correlating the formation of a nuclease hypersensitive site with the assembly of MSL complexes, roX2 also has an internal sequence that functions to recruit MSL complexes and is hypersensitive in male but not in female flies (Greenberg, 2004).

In light of the effects of Trl mutations on male viability, it is interesting to note that the internal nuclease hypersensitive site in the roX1 and roX2 genes harbors potential GAGA-factor-binding sites. Moreover, these potential GAGA-binding sites appear to be important for the entry site function of these elements. However, no GAGA was detected at roX2, and although GAGA does appear to be localized close to roX1, it did not significantly overlap with the roX1 Msl complex in confocal experiments. In this case, why was GAGA protein not detected at either the roX1 or the roX2 entry sites in polytene chromosomes? It is possible that the amount of GAGA factor at these two sites is too low to be detected or that the protein is inaccessible to the GAGA antibody because of the Msl complex. Alternatively, the GAGA factor might be required for the initial formation of the roX1/roX2 hypersensitive sites, but would then be largely displaced when the MSL complexes are assembled. In this case it would be required for establishment, not maintenance. Finally, it is also possible that it is not the GAGA factor but one of the other fly proteins that binds to the (GA)n/(CT)n motifs in roX1 and roX2. Clearly, further studies will be required to resolve this question (Greenberg, 2004).


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Trithorax-like: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation

date revised: 20 July 2013

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