Abstract
BackgroundMaintenance 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.ResultsWe show 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.ConclusionsWe propose 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.
Highlights
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) contains a bipartite site for interaction with SET domains of both E(z) and Trx Genetic analysis suggests that Asx is required for both trithorax group (trxG) and Polycomb group (PcG) function
No genetic experiment can show that Asx has a direct effect on the histone methyltransferases (HMT) responsible for trimethylation of H3K4 and H3K27
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. In Drosophila melanogaster, Asx was originally identified as a PcG mutant because of prominent posterior transformations caused by derepression of Hox genes [4,5,6]. It was observed that embryos mutant for Asx exhibit both anterior and posterior transformations, Various enzymatic activities are associated with trxG and PcG proteins, including trimethylation of histone H3 lysine 4 (H3K4) and H3K27 [13, 14]. One model to explain the ETP function of Asx is that it interacts directly with E(z) and Trx to regulate H3K4 and H3K27 methylation. Neither of these models has been tested on Asx or its mammalian homologs, perhaps because of difficulty of identifying a single locus at which both PcG and trxG proteins act at the same time in the same cell
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