Disease relevance of trx

• Cysteine-rich portions expressed from trx cDNAs in Escherichia coli are capable of zinc binding in vitro, suggesting a possible function for the trx product as a metal-dependent DNA-binding protein [1].
• MLL5, a homolog of Drosophila trithorax located within a segment of chromosome band 7q22 implicated in myeloid leukemia [2].
• Loss of en expression in the dorsal fat body is correlated with the sterility of en females which also carry trx mutations [3].
• Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias [4].

High impact information on trx

• Polycomb and trithorax group proteins mediate the function of a chromatin insulator [5].
• Trithorax and dCBP acting in a complex to maintain expression of a homeotic gene [6].
• Trithorax (Trx) is a member of the trithorax group (trxG) of epigenetic regulators, which is required to maintain active states of Hox gene expression during development [6].
• Trithorax (TRX) is a Drosophila SET domain protein that is required for the correct expression of homeotic genes [7].
• We found that this mutation selectively interferes with histone binding, suggesting that histones represent a critical target during developmental gene regulation by TRX [7].

Biological context of trx

• Genetic evidence suggests that trx may be considered a positive regulator of homeotic genes [1].
• Sequencing of cDNAs corresponding to the entire trx transcription unit revealed the existence of an unusually long open reading frame encoding 3759 amino acids [1].
• P-element mediated transformation using 34 kb of genomic DNA containing the 25 kb trx transcription unit identifies all sequences necessary for normal trx function and limits the 5' and 3' flanking sequences that could be used in a regulatory capacity to relatively small regions [8].
• Trithorax binding occurs within an 8.4-kb regulatory region that directs fork head expression in several embryonic tissues including salivary glands [9].
• A strong trithorax binding site was found at the cytological location of the fork head gene, a region-specific homeotic gene not located within a homeotic complex [9].

Anatomical context of trx

• Using a Drosophila haploid cell line for transient expression, we found that trithorax or Polycomb can function independently through this upstream fragment to activate or repress the Ultrabithorax promoter, respectively [10].
• Like the homeotic genes, en expression is dependent on trx in only a subset of embryonic cells normally expressing en, including specific cells in the nervous system and the dorsal fat body cells surrounding the gonad [3].
• Indeed, transcription of bithorax complex genes in the mesoderm and ectoderm is altered in strong trithorax mutants during germ band elongation, while the anteriorly expressed Antennapedia complex genes are affected only at late stages of embryonic development [11].
• At cellular blastoderm, trithorax RNA expression in D. virilis embryos is also confined to the posterior portion of the presumptive mesoderm [12].
• Chromatin immunoprecipitation revealed that testis TAFs bind to target promoters, reduce Polycomb binding, and promote local accumulation of H3K4me3, a mark of Trithorax action [13].

Associations of trx with chemical compounds

• These very large trx proteins differ only in a long Ser- and Gly-rich N-terminal extension, encoded by exon II, which is present only in the larger trx isoform [14].
• Trithorax interacts with type 1 serine/threonine protein phosphatase in Drosophila [15].
• ASH1, a Drosophila trithorax group protein, is required for methylation of lysine 4 residues on histone H3 [16].
• One of these includes a cysteine repeat motif that is similar to a motif found in Drosophila Nervy and the human MTG8 proto-oncoprotein, and another matches a region of Drosophila Trithorax [17].
• The direct interaction between ASH2, a Drosophila trithorax group protein, and SKTL, a nuclear phosphatidylinositol 4-phosphate 5-kinase, implies a role for phosphatidylinositol 4,5-bisphosphate in maintaining transcriptionally active chromatin [18].

Physical interactions of trx

• PP1beta9C interacts with Trithorax in Drosophila wing development [19].
• Surprisingly, the majority of the subunits of the BRM complex are not encoded by trithorax group genes [20].
• We localized one trithorax binding site within a portion of the large 5' regulatory region of the Ubx gene, to an interval which also contains binding sites for Polycomb group proteins [21].
• The Drosophila trithorax protein binds to specific chromosomal sites and is co-localized with Polycomb at many sites [21].
• Characterization of the extended Myb-like DNA-binding domain of trithorax group protein Zeste [22].

Other interactions of trx

• At the same stage, TRX but not PC is strongly associated with core promoters [23].
• In addition, we have identified the minimal fragments from the Ultrabithorax (Ubx) regulatory region that are capable of recruiting TRX to chromosomal sites containing them [23].
• We show that trx does indeed exert its effects by positively regulating homeotic gene expression and that its effects on expression of individual homeotic genes are complex: each of the BX-C and ANT-C genes examined exhibits different tissue-specific, parasegment-specific and promoter-specific reductions in their expression [24].
• Direct binding was demonstrated by GST pull-down experiments and PP1beta9C/TRX interaction in vivo was confirmed by coimmune precipitation from Drosophila embryonic extracts [19].
• These results also imply that those components of homeotic gene expression patterns for which trx is dispensable, require other factors, possibly those encoded by other trithorax-like genes [24].

Analytical, diagnostic and therapeutic context of trx

• Dissection of one of these maintenance modules showed that TRX- and Polycomb-group responsiveness is conferred by neighboring but separable DNA sequences, suggesting that independent protein complexes are formed at their respective response elements [25].
• Interaction between PP1c and TRX was confirmed in vivo by co-immunoprecipitation from Drosophila extracts [15].
• This work represents the first microarray analysis, to our knowledge, of a trithorax-group gene [26].
• Although sequence analysis indicates that the EST41159 gene product is novel, a region of amino acid identity with sequences of a yeast polypeptide of, as yet, unknown function and the Drosophila trithorax protein suggests the presence of an evolutionarily and functionally conserved domain [27].

References