absent, small, or homeotic discs 1
Mutations in the ash-1 and ash-2 genes of Drosophila cause a wide variety of homeotic transformations that are similar to the transformations caused by mutations in the trithorax gene. Based on this similar variety of transformations, it was hypothesized that these genes are members of a functionally related set. Three genetic tests were employed here to evaluate that hypothesis. The first test was to examine interactions of ash-1, ash-2 and trithorax mutations with each other. Double and triple heterozygotes of recessive lethal alleles express characteristic homeotic transformations. For example, double heterozygotes of a null allele of ash-1 and a deletion of trithorax have partial transformations of their first and third legs to second legs and of their halteres to wings. The penetrance of these transformations is reduced by a duplication of the bithorax complex. The second test was to examine interactions with a mutation in the female sterile (1) homeotic gene. The penetrance of the homeotic phenotype in progeny from mutant mothers is increased by heterozygosis for alleles of ash-1 or ash-2 as well as for trithorax alleles. The third test was to examine the interaction with a mutation of the Polycomb gene. The extra sex combs phenotype caused by heterozygosis for a deletion of Polycomb is suppressed by heterozygosis for ash-1, ash-2 or trithorax alleles. The fact that mutations in each of the three genes give rise to similar results in all three tests represents substantial evidence that ash-1, ash-2 and trithorax are members of a functionally related set of genes (Shearn, 1989).
ash1 is one of the trithorax complex genes. Recessive loss of function mutations in ash1 cause homeotic transformations of imaginal disc-derived tissue that resemble phenotypes caused by partial loss or gain of function mutations in genes of the Antennapedia and bithorax complexes. Mutations in the gene brahma, itself a member of the trithorax complex, interact with mutations in ash1 such that non-lethal ash1 +/+ brm double heterozygotes have a high penetrance of homeotic transformations in specific imaginal disc- and histoblast- derived tissues (Tripoulas, 1994).
The determined state of Drosophila imaginal discs depends on stable patterns of homeotic gene expression. The stability of these patterns requires the function of the ash1 gene, a member of the trithorax group. The nucleotide sequence alterations in 10 ash1 mutant alleles and their mutant phenotypes have been examined. The best candidate for a null allele is ash1. The truncated protein product of this mutant allele is predicted to contain only 47 amino acids. The ASH1 protein is localized on polytene chromosomes of larval salivary glands at > 100 sites. The chromosomal localization of ASH1 implies that it functions at the transcriptional level to maintain the expression pattern of homeotic selector genes (Tripoulas, 1996).
The Mod(mdg4) protein is present at approximately 500 sites on polytene chromosomes of third-instar larvae from strains that lack gypsy elements. Many or all of these sites might represent endogenous insulators. Since both Mod(mdg4) and su(Hw) associate with the gypsy insulator, it is possible that they colocalize at many of these sites. su(Hw) is a DNA binding protein and Mod(mdg4), unable to bind DNA, has been shown to be able to physically interact with su(Hw), thus facilitating the association of Mod(mdg4) with the insulator. The su(Hw) protein is present at approximately 200 sites on polytene chromosomes, and Mod(mdg4) is found at every one of these sites. Since the gypsy retrotransposon is not present at these sites, it is hypothesized that these chromosomal locations contain sequences similar to those present in the gypsy insulator and are thus functionally equivalent. The Mod(mdg4) protein is present in approximately 300 additional sites without su(Hw), suggesting that Mod(mdg4) can interact with DNA-binding proteins other than su(Hw), either to form a different type of insulator or to play a different role in gene expression. Indeed, Trithorax group and Polycomb group proteins are found to colocalize with Mod(mdg4) at some sites on polytene chromosomes. Mutations in trithorax, absent small or homeotic discs1 (ash1) and brahma reduce the levels of Mod(mdg4) protein in polytene chromosomes. The punctated pattern of Mod(mdg4) in the nuclei of follicle cells is lost in su(Hw) mutants. It is thought that the functional domains represented by these subnuclear regions is nuclear matrix. This opens the possibility that insulator sequences act as matrix attachment regions and that su(Hw) and Mod(mdg4) mediate the interaction of boundary elements with the nuclear matrix. Interestingly, in the background of a null mutation in the su(Hw) gene, the Mod(mdg4) protein is not found at those sites that are common with su(Hw), whereas localization at other sites appears normal. The subnuclear distribution of Mod(mdg4) and su(Hw) is dramatically altered in the background of trithorax Group mutations, with a loss of the punctated pattern. In trxG mutants Mod(mdg4) localizes mostly to the cytoplasm. In polycomb mutants Mod(mdg4) and su(Hw) localize to the central region of the nucleus instead of the nuclear matrix. The alterations in the subnuclear localization of Mod(mdg4) and Su(HW) proteins as a consequence of mutations in trxG and PcG genes correlate with the effects these mutations cause on insulator function (Gerasimova, 1998).
The proteins encoded by two groups of conserved genes, the Polycomb and trithorax groups, have been proposed to maintain, at the level of chromatin structure, the expression pattern of homeotic genes during Drosophila development. To identify new members of the trithorax group, a collection of deficiencies were screened for intergenic noncomplementation with a mutation in ash1, a trithorax group gene. Five of the noncomplementing deletions uncover genes previously classified as members of the Polycomb group. This evidence suggests that there are actually three groups of genes that maintain the expression pattern of homeotic genes during Drosophila development. The products of the third group appear to be required to maintain chromatin in both transcriptionally inactive and active states. Six of the noncomplementing deficiencies uncover previously unidentified trithorax group genes. One of these deficiencies removes 25D2-3 to 26B2-5. Within this region, there are two allelic, lethal, P-insertion mutations that identify one of these new trithorax group genes. The gene has been called little imaginal discs based on the phenotype of mutant larvae. The protein encoded by the little imaginal discs gene is the Drosophila homolog of human retinoblastoma binding protein 2 (Gildea, 2000).
When heterozygous, trithorax mutations cause either no transformations or an extremely low frequency of transformations of the third thoracic segment to the second segment. However, when homozygous, trithorax mutations cause transformations of the first and third thoracic segments to the second segment and anterior transformations of the abdominal segments. Other genes in which mutations cause similar phenotypes have been classified as members of the trithorax group. Trithorax group genes have been identified by several approaches. Two of the trithorax group genes, ash1 and ash2, were identified as pupal lethal mutations that disrupt imaginal disc development. Most of the other trithorax group genes were identified in a genetic screen for dominant suppressors of the adult phenotypes of dominant Polycomb or Antennapedia mutations. Like mutations in Polycomb group genes, mutations in trithorax group genes show intergenic noncomplementation, i.e., heterozygosis for recessive mutations in two different trithorax group genes can cause an adult mutant phenotype. The phenotype can include partial transformations of the first and third thoracic segments to the second thoracic segment and partial anterior transformations of the abdominal segments. The similar phenotypes of mutations in trithorax group genes and their intergenic noncomplementation has suggested that the products of these genes also act via multimeric protein complexes. Indeed, a 2-MD complex has been detected in embryos that contains the products of the trithorax group genes, brahma. However, this complex does not contain the products of the trithorax group gene ash1, which is in a different 2-MD complex, which also contains the product of the trithorax gene, nor does this complex contain the product of ash2, which is in a 0.5-MD complex. Taking advantage of the phenomenon of intergenic noncomplementation, a large fraction of the Drosophila genome was screened to look for new trithorax group genes. Females heterozygous for an ash1 mutation were crossed to males heterozygous for one of 133 deficiencies and the progeny doubly heterozygous for the ash1 mutation and the deficiency for homeotic transformations were examined. In this way regions of the genome with candidate trithorax group genes were identified (Gildea, 2000).
Six of the deficiencies uncovered genes that were previously classified in the Polycomb group. They were so classified, because they either enhanced the Polycomb mutant phenotype or caused a phenotype like Polycomb mutants. This result was quite unexpected because the antagonism between trithorax and Polycomb group genes suggested that loss of function of Polycomb group genes should suppress trithorax mutant phenotypes, while these deficiencies showed an enhancement of trithorax group mutant phenotypes. Nevertheless it is likely that the Polycomb group genes uncovered by these deficiencies are responsible for the observed intergenic noncomplementation with ash1RE418. It was thought possible that the observed intergenic noncomplementation is specific for ash1 mutations rather than general for mutations in trithorax group genes. This possibility was excluded for four of the five genes by showing that E(Pc)1, Psc1, Su(z)21, AsxXF23, Asx3, and Asx13 also show intergenic noncomplementation with trxb11 and/or brm2 and increase the penetrance of two different double mutants: ash1VF101 trxb11 and brm2 trxe2. It has also been reported that Asx mutations show intergenic noncomplementation with mutations in trithorax group genes. In some of these cases, the different mutant alleles tested give inconsistent results. For example, both ScmD1 and Scmm56 show intergenic noncomplementation with ash1VV183 and enhance the phenotype of the ash1VF101 trxb11 double mutant, whereas Scm302 does not enhance the phenotype of ash1VV183 and suppresses the phenotype of ash1VF101 trxb11. It is supposed that this difference is due to differences in the specific alterations of the Scm protein caused by these mutations (Gildea, 2000).
Until now the antagonism of function between the products of Polycomb group genes and trithorax group genes has been demonstrated unidirectionally by the suppression of Polycomb group mutant phenotypes by mutations in trithorax group genes. Advantage was taken of the intergenic noncomplementation of mutations in trithorax group genes to assay suppression of trithorax group mutant phenotypes by mutations in genes previously classified as Polycomb group genes. Among ash1VF101;trxb11 and brm2;trxe2 double heterozygotes, 52% and 35%, respectively, of adult flies express transformations of the third thoracic segment to the second thoracic segment. Most mutations in seven of the genes that have been classified as members of the Polycomb group (Polycomb, polyhomeotic, pleiohomeotic, Polycomb-like, multi sex combs, extra sex combs, and Super sex combs) suppress the penetrance of these transformations, in both of these double heterozygotes. Moreover, most mutations in these genes do not show intergenic noncomplementation with mutations in any of the three trithorax group genes that have been tested. It is suggested that these genes represent the Polycomb group defined here as genes in which loss-of-function mutations enhance the dominant phenotype caused by Polycomb mutations and suppress the phenotype caused by heterozygosity for double mutations in trithorax group genes such as ash1VF101;trxb11 and brm2;trxe2 (Gildea, 2000).
The zeste (z) gene encodes a transcription factor that binds DNA in a sequence-specific manner. The z1 mutation causes reduced white gene transcription. Mutations in three genes identified as dominant modifiers of the zeste-white interaction, Enhancer of zeste, Suppressor of zeste-2, and Sex comb on midleg, can also cause phenotypes like mutations in Polycomb group genes. Here it is shown that mutations in these three genes also behave as mutations in trithorax group genes: they show intergenic noncomplementation with mutations in trithorax group genes and/or increase the penetrance of ash1VF101;trxb11 and/or brm2;trxe2 heterozygotes. Moreover, mutations in three other genes identified as suppressors of the zeste-white interaction, Suppressor of zeste-4, Suppressor of zeste-6, and Suppressor of zeste-7, may show intergenic noncomplementation with mutations in trithorax group genes and/or increase the penetrance of ash1VF101;trxb11 heterozygotes. The biochemical mechanism by which mutations in these genes modify the zeste-white interaction is not known. However, it is thought to be significant that many of the genes identified as Suppressors of zeste behave as if they are both trithorax and Polycomb group genes; that Enhancer of Polycomb is a suppressor of zeste, and that sex combs extra is an enhancer of zeste (Gildea, 2000).
It is proposed that the six genes (previously classified as Polycomb group genes) belong in a distinct group; in these genes, loss-of-function or antimorphic mutations show intergenic noncomplementation with mutations in trithorax group genes and increase the penetrance caused by double heterozygosis of mutations in trithorax group genes. It is proposed that this group be called the ETP (Enhancers of trithorax and Polycomb mutations) group. Loss-of-function mutations in this group of genes not only enhance the dominant phenotype caused by Polycomb mutations, as do mutations in Polycomb group genes but they also enhance the phenotype caused by heterozygosity for double mutations in trithorax group genes, such as ash1VF101;trxb11 and brm2;trxe2, as do mutations in trithorax group genes (Gildea, 2000).
Mutations in many of the genes that have been classified in the ETP group lead to ectopic expression of homeotic genes in embryos. It has been inferred from such results that the normal function of the products of these genes is to repress transcription. However, a recent study of the consequences of mutations in one of these genes, Enhancer of zeste, demonstrated both ectopic expression and loss of expression of the same homeotic genes. That study was made possible by the availability of a strong temperature-sensitive allele. Without such alleles it would be very difficult to directly assay other members of the group for loss of homeotic gene expression. Nevertheless, the enhancement of the phenotype of mutations in both Polycomb and trithorax group genes by loss-of-function mutations in genes of the ETP group is interpreted as an indication that the products of these genes are required for both activation and repression of transcription. It has been proposed that the product of the zeste gene itself is also involved in both activation and repression of transcription. Little information is available on the biochemical mechanism of action of any of these genes. There is evidence of a multimeric protein complex containing the products of the Polycomb group genes, Polycomb and Polyhomeotic, and of three different complexes containing the products of the trithorax group genes, brahma, ash1, and ash2. One way of rationalizing how mutations in the ETP group of genes could behave as both Polycomb and trithorax group mutations would be to suggest that the products of the ETP genes are components of complexes required for both repression and activation. Perhaps they are responsible for the structure of these complexes or different protein variants encoded by these genes are components of different complexes. Although Polycomb and trithorax group genes were first identified in Drosophila, homologous genes exist in mammals. Until now, most interpretations of the functions of the products of such genes have been based on the idea that the products of Polycomb group genes repress gene transcription and the products of trithorax group genes activate gene transcription. The data presented here together with earlier data suggest that some of the genes previously classified as Polycomb group genes and at least some of the genes identified as suppressors or enhancers of zeste belong to a group of genes whose products play a role in both the repression and activation of gene transcription. These data will require new interpretations of the functions of such genes (Gildea, 2000).
The products of trithorax group (trxG) genes maintain active transcription of many important developmental regulatory genes, including homeotic genes. Several trxG proteins have been shown to act in multimeric protein complexes that modify chromatin structure. Ash2, the product of the Drosophila trxG gene absent, small, or homeotic discs 2 (ash2) is a component of a 500-kD complex. ASH2 binds directly to Skittles (Sktl), a predicted phosphatidylinositol 4-phosphate 5-kinase, and the association of these proteins is functionally significant. Histone H1 hyperphosphorylation is dramatically increased in both ash2 and sktl mutant polytene chromosomes. These results suggest that Ash2 maintains active transcription by binding a producer of nuclear phosphoinositides and downregulating histone H1 hyperphosphorylation (Cheng, 2004).
Ash2 does not accumulate on ash1 mutant chromosomes, but Ash1 still accumulates on ash2 mutant chromosomes. This suggests that Ash2 needs Ash1 to bind chromosomes. It is predicted that Sktl will not be able to bind to ash1 mutant chromosomes, since Sktl requires Ash2 and Ash2 requires Ash1 to bind to chromosomes. This could also explain why intergenic noncomplementation is seen between ash1 and sktl mutations (Cheng, 2004).
Covalent modifications of histone tails modulate gene expression via chromatin organization. As examples, methylation of lysine 9 residues of histone H3 (H3) (H3-K9) is believed to repress transcription by compacting chromatin, whereas methylation of lysine 4 residues of H3 (H3-K4) is believed to activate transcription by relaxing chromatin. The Drosophila trithorax group protein Absent, small, or homeotic discs 1 (Ash1) is involved in maintaining active transcription of many genes. In extreme ash1 mutants, no H3-K4 methylation is detectable. This lack of detectable H3-K4 methylation implies that Ash1 is required for essentially all H3-K4 methylation that occurs in vivo. The 149-aa SET domain of ASH1 is sufficient for H3-K4 methylation in vitro. These findings support a model in which ASH1 is directly involved in maintaining active transcription by conferring a relaxed chromatin structure (Byrd, 2003).
The extent of H3-K4 methylation, observed by immunofluorescence on polytene chromosomes from ash1 mutants, correlates extremely well with that observed by immunoblotting of salivary gland extracts. Immunofluorescence on polytene chromosomes provides qualitative information about the genomic distribution of H3-K4 methylation in addition to quantitative information about the extent of H3-K4 methylation. By using immunofluorescence on polytene chromosomes from salivary glands and immunoblotting of salivary gland extracts, it has been shown that detectable H3-K4 methylation is essentially eliminated by strong ash1 mutations. This lack of detectable H3-K4 methylation in ash 1 mutants indicates that Ash1 is required for H3-K4 methylation, but it does not indicate whether that requirement is direct. One possibility is that histone integrity is destroyed in ash1 mutants, and the failure to detect H3-K4 methylation is only a secondary consequence. This possibility was ruled out by showing that in those same mutants histone acetylation and methylation of other residues is not affected. Ash1 is a component of a multimeric protein complex; another possibility is that some other component of the complex is responsible for histone methylation. In the antimorphic alleles where no full-length Ash1 protein can accumulate, the complex might not form and thus prevent another component from functioning. One argument against this possibility is that in the missense mutant ash110, no methylation of H3-K4 is detected despite the accumulation of normal amounts of full-length Ash1 protein on polytene chromosomes. However, an even stronger argument against this possibility is that fragments of Ash1 can methylate H3-K4 in vitro, so the evidence is that Ash1 is required directly for virtually all of the H3-K4 methylation that occurs in vivo (Byrd, 2003).
In wild-type polytene chromosomes the vast majority of H3 methylated on lysine 9 residues is located in the chromocenter. In Su(var)3-9 mutants, there is strongly reduced accumulation of methylated H3-K9 in the chromocenter. It is evident, however, that Su(var)3-9 is not the sole HMTase with specificity for H3-K9 in Drosophila, because there is still some H3-K9 methylation on chromosomes from Su(var)3-9 null mutants. Su(var)3-9 null mutants are viable, affecting only position effect variegation, suggesting that the catalytic activity of Su(var)3-9 alone is not sufficient for global gene silencing. There is also significantly reduced accumulation of methylated H3-K9 at the chromocenter of ash1 mutants. This was surprising, because Ash1 is not known to play any role in heterochromatic gene silencing. Perhaps Ash1 plays a role in gene silencing in combination with SU(VAR)3-9 that has yet to be discovered. In any case, this means that Ash1 is one of at least two enzymes that can catalyze methylation of H3-K9. This is consistent the observation that a 588-aa fragment of Ash1 can methylate both K4 and K9 residues of H3 in vitro. However, little H3-K9 methylation is detected outside of the chromocenter on wild-type chromosomes. The pattern of H3-K9 methylation observed is completely different from the pattern of H3-K4 methylation, which is not consistent with the idea that Ash1 catalyzes the methylation of both K4 and K9 on the same H3 molecules. One possible explanation of this discrepancy is that Ash1 catalyzes only a small fraction of the H3-K9 that occurs in vivo, and that the amount of H3-K9 methylation in the chromocenter catalyzed by SU(VAR)3-9, Ash1, and possibly other enzymes overwhelms the ability to detect any on the chromosome arms. A widespread distribution of acetylated H3-K9 is detected on chromosome arms. If Ash1 methylates H3-K9 along chromosome arms, it might have been expected that the level of H3-K9 acetylation would increase in ash1 mutants, because the absence of methylation would increase the availability of free H3-K9 residues. However, no such increase was observed. The 588-aa Ash1 fragment can also catalyze a low level of methylation of H4-K20. A widespread distribution of methylated H4-K20 along the chromosome arms is observed. However, no loss of H4-K20 methylation was observed even in the strongest ash1 mutants. If Ash1 catalyzes H4-K20 methylation in vivo, it must catalyze only a small fraction of the total H4-K20 methylation that occurs (Byrd, 2003).
The SET domain of Ash1 is important for HMTase activity. The ash110 allele that has a substitution within the SET domain (N1385I) causes absence of H3-K4 methylation. The significance of this conserved asparagine for the HMTase activity of the Ash1 SET domain is underscored by evidence that H3-K4 methylase activity of a 588-aa Ash1 fragment is lost when this same substitution is introduced. The finding that the ash121 allele that has a substitution within the preSET domain (E1248K) causes reduction but not elimination of H3-K4 methylation suggests that the preSET domain may affect the efficiency of methylation but is not essential for activity. This conclusion is supported by data showing that the SET domain by itself (residues 1300-1448) can methylate H3-K4 in vitro. However, this conclusion is not supported by a report that the H3-K4 methylase activity of a 588-aa Ash1 fragment (1032-1619) is lost when this same substitution (E1248K) is introduced. It has also been reported that the 588-aa fragment of Ash1 can methylate H3-K9 residues. The 149-aa SET domain contained within that 588-aa fragment cannot methylate H3-K9 residues, suggesting that the preSET and postSET domains add functionality required for H3-K9 methylation (Byrd, 2003).
Lysine residues can be mono-, di-, or tri-methylated. Recent evidence suggests that, at least in Saccharomyces cerevisiae, active genes are trimethylated. The antibody used to detect lysine 4 methylation of H3 was made against a peptide with a dimethylated lysine. It has the highest specificity for peptides with dimethylated lysine residues, but it can also detect peptides with mono- and tri-methylated lysine residues. Although the 149-aa SET domain of Ash1 can methylate H3-K4 in vitro, the methylation state of the product detected is not known. The in vivo function of Ash1 may be to mono- and/or dimethylate H3-K4 residues; di- and/or trimethylation may be the function of some other HMTase. If this is the case, then the absence of H3-K4 methylation found in extreme ash1 mutants means that the methylation function of Ash1 creates a substrate essential for subsequent methylation. Support for this idea comes from data showing that in ash2 null mutants, the extent of H3-K4 methylation is reduced, but the distribution is like wild-type. The human homologue of ASH2 is in a multimeric complex with SET1, a protein shown to have H3-K4 methylase activity. If Drosophila ASH2 is also in a complex with a SET1 homologue, then such a complex may be responsible for subsequent methylation of H3-K4 residues initially methylated by Ash1 (Byrd, 2003).
Genetic evidence has indicated that Ash1 is a member of the Trx group of proteins that is involved in maintaining active transcription of many genes. The activities of Ash1 and Trx are functionally related. Mutations in ash1 and trx exhibit intergenic noncomplementation; Ash1 and Trx colocalize at multiple sites on polytene chromosomes, and Ash1 can be coimmunoprecipitated from embryonic nuclear extracts by antibodies that recognize Trx. Moreover, Trx accumulation on polytene chromosomes is reduced in an ash1 mutant and to associate with a histone acetyltransferase, dCBP. These results, together with the results showing that Ash1 functions as an HMTase, suggest a model for the sequential order to Ash1 and Trx association and in turn histone methylation and acetylation. According to this model, Ash1 binds to H3 via its SET domain and methylates K4 residues. The SET domain of Trx recognizes these methylated H3-K4 residues, which could explain the loss of Trx on chromosomes from an ash1 mutant. Trx recruits dCBP, which can then acetylate nearby lysine residues. If this model were correct, one would expect that loss of Ash1 catalyzed methylation would secondarily cause loss of acetylation. The data, however, do not fulfill this expectation. In ash1 mutants, where the levels of H3-K4 methylation are barely detectable, the levels of acetylation on both H3 and histone H4 are unchanged as compared with wild type. Thus, site-specific changes in histone methylation due to disruption of ash1 have no apparent effect on histone acetylation. It could be, however, that only acetylation of residues that do not depend on methylation of H3-K4 were examined. Moreover, ash114, the mutant that showed reduced chromosomal Trx, has a molecular defect at nearly the same location as ash116. It is likely that ash114 also has a normal level of HMTase activity, which suggests that Trx requires the C-terminal domain of Ash1 rather than its HMTase activity to bind to chromosomes. Further work will be required to understand the molecular basis of the functional relationship between Ash1 and Trx and the roles of other components of the 2MDa Ash1 complex (Byrd, 2003).
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date revised: 10 October 2013
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