org Interactive Fly, Drosophila Enhancer of zeste: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation | References

Gene name - Enhancer of zeste

Synonyms - polycombeotic (pco)

Cytological map position - 67E 3-4

Function - transcription factor, enzyme

Keywords - Polycomb group, modifier of chromatin, histone methyltransferase

Symbol - E(z)

FlyBase ID:FBgn0000629

Genetic map position - 3-34.0

Classification - trithorax homology, histone methyltransferase

Cellular location - nuclear



NCBI links: Precomputed BLAST | Entrez Gene
Recent literature
Matsuoka, Y., Bando, T., Watanabe, T., Ishimaru, Y., Noji, S., Popadic, A. and Mito, T. (2015) Short germ insects utilize both the ancestral and derived mode of Polycomb group-mediated epigenetic silencing of Hox genes Biol Open. PubMed ID: 25948756
Summary:
In insect species that undergo long germ segmentation, such as Drosophila, all segments are specified simultaneously at the early blastoderm stage. As embryogenesis progresses, the expression boundaries of Hox genes are established by repression of gap genes, which is subsequently replaced by Polycomb group (PcG) silencing. At present, however, it is not known whether patterning occurs this way in a more ancestral (short germ) mode of embryogenesis, where segments are added gradually during posterior elongation. In this study, two members of the PcG family, Enhancer of zeste (E(z)) and Suppressor of zeste 12 (Su(z)12), were analyzed in the short germ cricket, Gryllus bimaculatus. Results suggest that although stepwise negative regulation by gap and PcG genes is present in anterior members of the Hox cluster, it does not account for regulation of two posterior Hox genes, abdominal-A (abd-A) and Abdominal-B (Abd-B). Instead, abd-A and Abd-B are predominantly regulated by PcG genes, which is the mode present in vertebrates. These findings suggest that PcG-mediated silencing of Hox genes may have occurred during animal evolution. The ancestral bilaterian state may have resembled the current vertebrate mode of regulation, where PcG-mediated silencing of Hox genes occurs before their expression is initiated and is responsible for the establishment of individual expression domains. Then, during insect evolution, the repression by transcription factors may have been acquired in anterior Hox genes of short germ insects, while PcG silencing was maintained in posterior Hox genes.
Xia, B., Gerstin, E., Schones, D.E., Huang, W. and Steven de Belle, J. (2016). Transgenerational programming of longevity through E(z)-mediated histone H3K27 trimethylation in Drosophila. Aging (Albany NY) 8: 2988-3008. PubMed ID: 27889707
Summary:
Transgenerational effects on health and development of early-life nutrition have gained increased attention recently. However, the underlying mechanisms of transgenerational transmission are only starting to emerge, with epigenetics as perhaps the most important mechanism. The first Drosophila model to study transgenerational programming of longevity after early-life dietary manipulations has been previously reported, enabling investigations to identify underlying epigenetic mechanisms. This study reports that post-eclosion dietary manipulation (PDM) with a low-protein (LP) diet upregulates the protein level of E(z), an H3K27 specific methyltransferase, leading to higher levels of H3K27 trimethylation (H3K27me3). This PDM-mediated change in H3K27me3 corresponds with a shortened longevity of F0 flies as well as their F2 offspring. Specific RNAi-mediated post-eclosion knockdown of E(z) or pharmacological inhibition of its enzymatic function with EPZ-6438 in the F0 parents improves longevity while rendering H3K27me3 low across generations. Importantly, addition of EPZ-6438 to the LP diet fully alleviates the longevity-reducing effect of the LP PDM, supporting the increased level of E(z)-dependent H3K27me3 as the primary cause and immediate early-life period as the critical time to program longevity through epigenetic regulation. These observations establish E(z)-mediated H3K27me3 as one epigenetic mechanism underlying nutritional programming of longevity and support the use of EPZ-6438 to extend lifespan.

Eun, S.H., Feng, L., Cedeno-Rosario, L., Gan, Q., Wei, G., Cui, K., Zhao, K. and Chen, X. (2017). Polycomb group gene E(z) is required for spermatogonial dedifferentiation in Drosophila adult testis. J Mol Biol [Epub ahead of print]. PubMed ID: 28434938
Summary:
Dedifferentiation is an important process to replenish lost stem cells during aging or regeneration after injury to maintain tissue homeostasis. This study reports that Enhancer of Zeste [E(z)], a component of the Polycomb Repression Complex 2 (PRC2), is required to maintain a stable pool of germline stem cells (GSCs) within the niche microenvironment. During aging, germ cells with reduced E(z) activity cannot meet that requirement, but the defect neither arises from increased GSC death nor premature differentiation. Instead, the decrease of GSCs upon inactivation of E(z) in the germline could be attributed to defective dedifferentiation. During recovery from genetically manipulated GSC depletion, E(z) mutant germ cells also fail to replenish lost GSCs. Taken together, these data suggest that E(z) acts intrinsically in germ cells to activate dedifferentiation and thus replenish lost GSCs during both aging and tissue regeneration.

Li, T., Hodgson, J. W., Petruk, S., Mazo, A. and Brock, H. W. (2017). Additional sex combs interacts with enhancer of zeste and trithorax and modulates levels of trimethylation on histone H3K4 and H3K27 during transcription of hsp70. Epigenetics Chromatin 10(1): 43. PubMed ID: 28927461
Summary:
Maintenance of cell fate determination requires the Polycomb group for repression; the trithorax group for gene activation; and the enhancer of trithorax and Polycomb (ETP) group for both repression and activation. Additional sex combs (Asx) is a genetically identified ETP for the Hox loci, but the molecular basis of its dual function is unclear. This study shows that in vitro, Asx binds directly to the SET domains of the histone methyltransferases (HMT) Enhancer of zeste [E(z)] (H3K27me3) and Trx (H3K4me3) through a bipartite interaction site separated by 846 amino acid residues. In Drosophila S2 cell nuclei, Asx interacts with E(z) and Trx in vivo. Drosophila Asx is required for repression of heat-shock gene hsp70 and is recruited downstream of the hsp70 promoter. Changes in the levels of H3K4me3 and H3K27me3 downstream of the hsp70 promoter in Asx mutants relative to wild type show that Asx regulates H3K4 and H3K27 trimethylation. It is proposed that during transcription Asx modulates the ratio of H3K4me3 to H3K27me3 by selectively recruiting the antagonistic HMTs, E(z) and Trx or other nucleosome-modifying enzymes to hsp70.
BIOLOGICAL OVERVIEW

A particular region (or domain) on the Enhancer of zeste protein has been shown to be responsible for gene silencing. To complicate matters, the same domain has been shown to be homologous to Trithorax, a known transcription activator. How can this be? How can a domain presumably involved in gene silencing be homologous to one involved in activation? The sharing of a domain between E(z), a transcription repressor, and Trithorax, a gene activator raises certain questions for which answers are not yet forthcoming: Which functions are located in the homologous region, and is their action competitive at the promoter binding site, or in interaction with the transcription apparatus, or with other proteins?

Two lines of evidence classify E(z) as a member of the trithorax group (trx-g). Firstly, double heterozygous combinations of mutant E(z) and absent, small or homeotic discs 1 (ash1), a trx-g gene, express homeotic transformation phenotypes similar to those found in double heterozygous combinations of mutant trithorax and ash1 alleles. Secondly, within thoracic imaginal discs of larvae hemizygous for mutant alleles of E(z) there is complete loss of accumulation of homeotic proteins Sex Combs Reduced, Antennapedia, and Ultrabithorax and the segmentation protein Engrailed. Similar loss of accumulation of these proteins is observed in trx-g mutations (LaJeunesse, 1996).

E(z) acting as a Polycomb group protein acts in the repression of knirps and giant. Hunchback protein is required to initiate repression of these genes, while E(z) secures and maintains such repression, in conjunction with the other PC-G proteins (Pelegri, 1995). Suppressor of zeste 2 and Posterior sex combs both partner E(z) in its role as a gene repressor. All three of these proteins dissociate from the chromosomes when a temperature sensitive E(z) mutant is inactivated by high temperatures. Gene silencing is lost in this circumstance as polytene chromosomes become decondensed at higher temperatures. Dissociation and decondensation occurs only a few hours after placing flies in non-permissive temperatures. This is graphic evidence that different PC-G proteins co-operate in a multi-protein complex. Inactivation of one protein causes the release of all from their chromosomal association (Rastelli, 1993).

Evidence is presented for direct physical interaction between the Extra sex combs (Esc) and E(z) proteins using yeast two-hybrid and in vitro binding assays. Coimmunoprecipitation from embryo extracts demonstrates association of Esc and E(z) in vivo. The Esc-binding domain of E(z) has been delimited to an N-terminal 33-amino-acid region. Only 6 of 33 amino acids in this region are identical among fly E(z), the murine homologs Ezh1 and Ezh2, and the human homologs EZH1 and EZH2. Site-directed mutations in the Esc protein previously shown to impair Esc function in vivo disrupt Esc-E(z) interactions in vitro. An in vitro interaction also occurs between the human eed (heed) and EZH1 proteins, which are human homologs of Esc and E(z), respectively. The amino acid sequences among these E(z) homologs are much more highly conserved in domains outside the 33 amino acid region. This result suggests that amino acids other than those that are evolutionarily conserved between E(z) and EZH1 participate in the interaction with Esc. It also suggests that Esc residues outside the absolutely conserved portions of the loops connecting blades 3, 4, and 5 of the WD repeat region are involved in binding to E(z) and EZH1. Additional studies will be required to further map the interacting domains of heed and EZH1 and to demonstrate their in vivo association. These results suggest that the Esc-E(z) molecular partnership has been conserved in evolution. Previous studies suggested that Esc is primarily involved in the early stages of Pc-G-mediated silencing during embryogenesis. However, E(z) is continuously required in order to maintain chromosome binding by other Pc-G proteins. In light of these earlier observations and the molecular data presented here, the paper discusses how Esc-E(z) protein complexes may contribute to transcriptional silencing by the Pc-G (Jones, 1998).

At least two lines of evidence indicate that Drosophila E(z) and Esc are not obligate partners at all loci and during all developmental stages. (1) Although both proteins display uniform spatial distributions in nuclei of blastoderm and early gastrulation-stage embryos, the Esc protein is much more limited than E(z) in mid-to-late-stage embryos. (2) There are target genes other than homeotic genes that require E(z), but not Esc, for repression during development. These examples show that the E(z) protein can be recruited to and function at target loci without assistance from the Esc protein. Presumably, E(z) action at these loci involves alternative binding partners. The ability of E(z) to sometimes act independently of Esc is one possible explanation for the differential efficiencies of reciprocal coimmunoprecipitations observed with the two proteins. It has been suggested that in addition to its role in Pc-G repression, E(z) may also be involved in the maintenance of transcriptional activity by trithorax-Group proteins. In contrast, the known role of the Esc protein is limited to repression. A dual role for E(z) could reflect participation in more than one type of protein complex. For example, when E(z) is bound to Esc, it is a component of silencing complexes. However, when E(z) is associated with other, as-yet-unidentified proteins, it may contribute to trx-G-mediated transcriptional activation. In support of this idea, heat inactivation of temperature-sensitive E(z) proteins reduces chromosomal binding by the Trx protein. To assess these possibilities, it will be necessary to define the number and constituents of E(z)-containing complexes isolated from fly embryos (Jones, 1998).

It was reasoned that Enhancer of zeste might reside in a protein complex that possess histone methyltransferase (MTase) activity. Pc contains a chromodomain whose structure and essential residues are homologous to those found in Hp1 and related methyl lysine binding proteins and might therefore recognize a nucleosomal methylation mark. E(z) complex have now been shown to contain an H3 MTase activity. To study the Esc/E(z) complex, Drosophila nuclear extract was fractionated and it was asked if a MTase activity copurifies with E(z) and Esc. A complex containing E(z) and Esc trimethylates lysine 9 and methylates lysine 27 of histone H3 and the trimethylated lysine 9 mark is closely correlated with PcG binding sites on polytene chromosomes. The conjecture that the Esc/E(z) complex contains a histone MTase activity has been confirmed by the finding that the complex immunoprecipitated by anti-Esc or purified biochemically methylates in vitro histone H3 whether assembled in a nucleosome, as a free histone, or in the form of oligopeptides. The purified complex contains several components as predicted from previous studies: in addition to E(z), Su(z)12, Esc, p55, and Rpd3 are found. An additional component of approximately 168 kDa remains to be identified (Czermin, 2002).

The activity of the Esc/E(z) complex leads to trimethylation of lysine 9 and probably also of lysine 27 of H3. In vivo, an antibody directed against dimethylated H3 lysine (9me2K9 antibody) does not detectably stain chromosomal PcG sites while a me3K9 antibody directed against trimethylated H3 lysine decorates all chromosomal PcG sites. Whether three methyl groups are added processively or by independent events and whether lysine 9 and lysine 27 are targeted simultaneously remains to be elucidated. The partial ability of the complex to methylate the peptide acetylated at lysine 9 is accounted for by the presence of the Rpd3 deacetylase (Czermin, 2002).

Polycomb complexes and the propagation of the methylation mark at the Drosophila Ubx gene

Polycomb group proteins are transcriptional repressors that control many developmental genes. The Polycomb group protein Enhancer of Zeste has been shown in vitro to methylate specifically lysine 27 and lysine 9 of histone H3 but the role of this modification in Polycomb silencing is unknown. This study shows that H3 trimethylated at lysine 27 is found on the entire Ubx gene silenced by Polycomb. However, Enhancer of Zeste and other Polycomb group proteins stay primarily localized at their response elements, which appear to be the least methylated parts of the silenced gene. These results suggest that, contrary to the prevailing view, the Polycomb group proteins and methyltransferase complexes are recruited to the Polycomb response elements independently of histone methylation and then loop over to scan the entire region, methylating all accessible nucleosomes. It is proposed that the Polycomb chromodomain is required for the looping mechanism that spreads methylation over a broad domain, which in turn is required for the stability of the Polycomb group protein complex. Both the spread of methylation from the Polycomb response elements, and the silencing effect can be blocked by the gypsy insulator (Kahn, 2006).

The experiments described in this study show clearly that all three PcG proteins tested, Pc, Psc, and E(z), are preferentially located at the PREs. This specificity is clearest and most sharply delineated in the case of Psc and E(z). In the case of PC, the peaks centered at the PREs are much broader, including secondary peaks, and although the binding detected at other Ubx regions decreases to low values, it never reaches the level seen at control sites such as the white gene that possess no PRE. The second basic conclusion from these experiments is that, in contrast to the localization of PcG proteins, the H3 me3K27 profile forms a broad domain that includes the entire Ubx transcription unit and upstream regulatory region. The third important observation is that, contrary to previously published accounts, the PREs themselves appear to contain the lowest levels of me3K27 of the entire domain. This surprising result will be considered first. The lack of apparent methylation at the PREs does not depend on the antibody used or on the level of cross-linking. Comparable results were obtained with two different anti-me3K27 antibodies and with anti-me3K9. Furthermore, the fact that a similar result was obtained with antibody against total histone H3 or histone H2B suggests that nucleosomes are underrepresented at the bxd PRE core. The result is not because of lack of accessibility to the histone or to the epitope: GAGA factor bound to the PRE appears as easily accessible as GAGA factor bound to the Ubx promoter. Salt extraction of the PcG complexes before cross-linking does not qualitatively change the me3K27 binding profile (Kahn, 2006).

In sum, careful quantitative analysis of ChIP indicates that while PcG proteins are principally localized at the PRE, the histone H3 methylation they produce is distributed over the entire Ubx gene. It is evident from this and from the undermethylation of the PRE core that that K27 methylation does not, by itself, recruit PcG complexes. This does not preclude an important role for methylation in PcG binding and silencing but suggests that the relationship between the two requires a more dynamic model (Kahn, 2006).

PREs have been shown to recruit PcG complexes and to produce new binding foci detectable in polytene chromosomes. It is not surprising therefore to find the three PcG proteins tested are associated with the two Ubx PREs. A much smaller peak in microarray profiles for all three proteins can be discerned in the vicinity of the Ubx 3'-exon but its significance is unknown. More surprising was the striking difference between the distributions of Psc and E(z) and that of Pc. E(z) and Psc belong to two different complexes that do not co-precipitate (except in the very early embryo) but are both recruited to the PRE. Pc and Psc are core components of the PRC1-type of PcG complex yet, while Psc is detected almost exclusively at the PREs, Pc has a much broader distribution peaking at the PREs but tailing over considerable distances along the Ubx gene and regulatory regions. The simplest interpretation of this is that a second type of complex containing Pc but not Psc is recruited by a different mechanism to the rest of the Ubx sequences. Alternatively, the same complex, containing both proteins is involved in both cases but the nature of the chromatin contact is different, such that in one case both proteins are well cross-linked to the chromatin but in the second case only Pc is efficiently cross-linked (Kahn, 2006).

Just as striking is the fact that, although the E(z) complex is responsible for the H3 K27 methylation spread over the entire Ubx gene, the E(z) protein is found localized at the PREs. It is concluded that the E(z) complex methylates the Ubx domain by a hit-and-run type of mechanism. Because the methylation is stable, the E(z) complex needs only visit each nucleosome once on the average every cell cycle. It is noted that E(z)-dependent histone H3 K27 dimethylation is highly abundant and widely distributed in the genome but E(z) complexes are not associated with it. Where then does the E(z) that methylates PcG target genes come from? While more complicated scenarios may be imagined, the simplest one involves the E(z) complex bound at the PRE (Kahn, 2006).

It is supposed that the PcG complexes are recruited to PREs by DNA-binding proteins independently of histone methylation. To methylate the entire Ubx domain, the E(z)/ESC histone MTase complex might then detach from the PRE and slide along the chromatin from one nucleosome to the next to survey the entire domain. However, it more likely that both the Pc and the E(z) complexes assembled at the PRE remain associated with the PRE sequences, where they are detected, but that the whole PRE assembly loops over to scan the entire region, methylating all accessible nucleosomes. Such looping models were originally proposed to be mediated by sites of weak PcG complex formation. In a modern version of this type of model, the looping activity would be mediated by the distinct affinity of the Pc protein for histone H3, which is greatly increased by K27 methylation. These affinities would mediate transient interactions of the complexes bound at the PRE with the surrounding chromatin and allow continuous scanning and methylation of unmethylated or hemimethylated nucleosomes (Kahn, 2006).

In such a model, ChIP experiments would always detect a strong PcG presence at the PRE but PcG interactions with the rest of the repressed gene would be distributed over a region, which is very large in the case of the Ubx gene, smaller in the case of the YGPhsW transposon, hence the signal detected at any one site would be weaker in proportion to the extent of the methylated domain. In addition, the contacts between the PcG complex and the rest of the silenced gene would be much more transient than contacts with the PRE. Together, these considerations would explain why ChIP assay gives such low values for PcG proteins over the rest of the methylated domain (Kahn, 2006).

The looping mechanism proposed for the PRE-bound complex strongly resembles that suggested for the interaction between the Locus Control Region and β-globin genes or for enhancer-promoter interactions. Like these interactions, the silencing of a promoter by the PRE is blocked by insulator elements. In transposon constructs, the insertion of a gypsy Su(Hw) insulator between PRE and promoter blocks the spread of methylation. At present, the mechanism of insulator action is not clear and how the block to methylation is achieved is unknown. It is possible that the insulator element produces topological constraints that prevent the PRE-bound complexes from looping beyond the insulator. This would be consistent with the observation that a significant level of Pc presence becomes detectable over the yellow gene when the insulator block is lifted (Kahn, 2006).

Although the data argue against a principal role of histone methylation in the recruitment of Polycomb proteins to their response elements, it seems to be important for both transcriptional repression and stable association of PcG proteins with chromatin. Loss of catalytic E(z) function eventually results in derepression of HOX genes and dissociation of PcG proteins from polytene chromosomes. It is speculated that once the me3K27 domain is established, modified nucleosomes will pave the way for looping interactions of the PRE-bound PcG proteins with the parts of the silenced gene including promoter or enhancer regions. Silencing might then result from hit-and-run interactions with either or both, possibly even resulting in methylation of the associated factors. Alternatively or in addition, trimethylation of K27 and possibly K9 may directly interfere with the signaling cascade of consecutive histone modifications that guide the multistep process of transcription initiation and elongation. Since histone methylation is thought to persist through cell division its immediate presence at the very beginning of the subsequent interphase might win the time necessary for the full assembly of PcG complexes on the PREs before competing transcription has taken over (Kahn, 2006).

A strand-specific switch in noncoding transcription switches the function of a Polycomb/Trithorax response element

Polycomb/Trithorax response elements (PRE/TREs) can switch their function reversibly between silencing and activation by mechanisms that are poorly understood. This study shows that a switch in forward and reverse noncoding transcription from the Drosophila melanogaster vestigial (vg) PRE/TRE switches the status of the element between silencing (induced by the forward strand) and activation (induced by the reverse strand). In vitro, both noncoding RNAs inhibit PRC2 histone methyltransferase activity, but, in vivo, only the reverse strand binds PRC2. Overexpression of the reverse strand evicts PRC2 from chromatin and inhibits its enzymatic activity. It is proposed that the interaction of RNAs with PRC2 is differentially regulated in vivo, allowing regulated inhibition of local PRC2 activity. Genome-wide analysis shows that strand switching of noncoding RNAs occurs at several hundred Polycomb-binding sites in fly and vertebrate genomes. This work identifies a previously unreported and potentially widespread class of PRE/TREs that switch function by switching the direction of noncoding RNA transcription (Herzog, 2014).

By analysis of endogenous transcripts and by using ectopic overexpression strategies in vivo it was demonstrated that transcripts from opposite strands of the vg PRE/TRE have opposite effects on PRE/TRE status. However, in vitro, both noncoding RNAs have equivalent inhibitory effects on the HMTase activity of PRC2. Taking the in vitro and in vivo data together, it is proposed that the specificity of the noncoding RNA interaction with PcG proteins in vivo is not a result of inherently different affinities of PRC2 for different noncoding RNAs but of the availability of a given noncoding RNA (regulated by interactions of that RNA with other molecules) to interact with PRC2 and inhibit its enzymatic activity. It is proposed that the forward-strand noncoding RNA promotes silencing by facilitating pairing between PRE/TREs. PRE/TRE pairing has been shown to be essential for maximum silencing by the vg PRE/TRE, and this silencing is genetically dependent on PcG. Thus, it is proposed that forward strand-induced pairing might facilitate or stabilize PcG-mediated pairing-dependent silencing. E(Z) is detected at the vg PRE/TRE in ChIP analyses but does not interact with the forward strand. Thus, it is proposed that E(Z) binds at the silenced PRE/TRE independently of RNA. The forward-strand noncoding RNA might facilitate or stabilize pairing by binding to additional bridging proteins. These or other proteins might also prevent binding and inhibition of E(Z) by the RNA (Herzog, 2014).

Upon switching to the active state, transcription of the reverse PRE/TRE strand would be incompatible with forward-strand transcription because the reverse transcript runs through the forward-strand promoter. Reverse-strand transcription might thus destabilize pairing, enabling the activation of the PRE/TRE. In addition, the reverse strand binds E(Z) and, upon binding, would inhibit E(Z) HMTase activity, and it might also remove E(Z) from the locus. In this way, multiple self-reinforcing events could contribute to the stable switching of the PRE/TRE into an active state. The vg PRE/TRE responds to TrxG mutations by loss of activation. Whether TrxG-dependent activation acts via the noncoding RNAs will be a key question for future studies (Herzog, 2014).

Genome-wide analysis identifies many sites that might share functional features with the vgPRE/TRE. It is proposed that these elements can exist in a 'neutral' state, in which neither they nor their associated genes are transcribed (this is consistent with the observation that the vg PRE/TRE is not transcribed in tissues or at embryonic stages that do not express vg mRNA). However, in tissues that have the potential to transcribe the gene, the element might be switched either to the forward or reverse mode, thereby boosting either silencing or activation. This might serve to sharpen spatial expression boundaries, to stabilize gene expression states or to accelerate the kinetics of activation or repression (Herzog, 2014).

In conclusion, this work provides a new paradigm linking forward and reverse noncoding transcription to dynamic and developmentally regulated switching of PRE/TRE properties and thus to the maintenance of cell identities during development. Furthermore, the demonstration that any RNA is a potent inhibitor of PRC2 enzymatic activity in vitro but that only specific RNAs are able to bind and inhibit PRC2 in vivo strongly implies that specific RNAs are masked in vivo from interacting with PRC2. This provides an enormous potential for the regulated and reversible RNA-mediated inhibition of local PRC2 activity (Herzog, 2014).


GENE STRUCTURE

Bases in 5' UTR - 103

Exons - seven

Bases in 3' UTR - 66


PROTEIN STRUCTURE

Amino Acids - 760

Structural Domains and Evolutionary Homologies

Molecular analysis of the Enhancer of zeste gene predicts a 760-amino-acid protein product. A region of 116 amino acids near the E(z) carboxy terminus is 41.2% identical (68.4% similar) to a carboxy-terminal region of the Trithorax protein. This portion of the Trithorax protein is part of a larger region previously shown to share extensive homology with a human protein (ALL-1/Hrx) implicated in acute leukemias. Over this same 116 amino acids, E(z) and ALL-1/Hrx are 43.9% identical (68.4% similar). Otherwise, E(z) is not significantly similar to any previously described proteins. Since this region of sequence similarity is shared by two proteins with antagonistic functions, it may comprise a domain that interacts with a common target, either nucleic acid or protein. Opposite effects on transcription might then be determined by other portions of the two proteins (Jones, 1993).

The C-terminal domain of Trx has been termed a tromodomain; the more generally accepted term for this is a SET domain (for Su(var)39, E(z) and trx, the three proteins in which the domain was first identified). With regard to the antagonistic functions between Trx and E(z), some E(z) mutants enhance the trx phenotypes rather than repressing them (Manuel Diaz, personal communication to the editor of The Interactive Fly).


Enhancer of zeste: Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation | References

date revised: 3 January 2003

Home page: The Interactive Fly © 1995, 1996 Thomas B. Brody, Ph.D.

The Interactive Fly resides on the
Society for Developmental Biology's Web server.