Specific gain- and loss-of-function phenotypes induced by satellite-specific DNA-binding drugs fed to Drosophila melanogaster

DNA-binding pyrrole-imidazole compounds were synthesized that target differ ent Drosophila melanogaster satellites. Compound P31 specifically binds the GAGAA satellite V, and P9 targets the AT-rich satellites I and ill. Remark ably, these drugs, when fed to developing Drosophila flies, caused gain- or loss-of-function phenotypes. While polyamide P9 (not P31) suppressed PEV o f white-mottled flies (increased gene expression), P31 (not P9) mediated th ree well-defined, homeotic transformations (loss-of-function) exclusively i n brown-dominant flies. Both phenomena are explained at the molecular level by chromatin opening (increased accessibility) of the targeted DNA satelli tes. Chromatin opening of satellite III by P9 is proposed to suppress PEV o f white-mottled flies, whereas chromatin opening of satellite V by P31 is p roposed to create an inopportune "sink" for the GAGA factor (GAF).