A rapid one-generation genetic screen in a Drosophila model to capture rhabdomyosarcoma effectors and therapeutic targets.
Bottom Line: Here, we report a new approach to dissect RMS, exploiting a highly efficient Drosophila PAX7-FOXO1 model uniquely configured to uncover PAX-FOXO1 RMS genetic effectors in only one generation.Additionally, we reveal that mutation of mastermind, a gene encoding a MEF2 transcriptional coactivator, similarly suppresses PAX7-FOXO1, further pointing toward MEF2 transcriptional activity as a PAX-FOXO1 underpinning.These studies show the utility of the PAX-FOXO1 Drosophila system as a robust one-generation (F1) RMS gene discovery platform and demonstrate how Drosophila transgenic conditional expression models can be configured for the rapid dissection of human disease.
Affiliation: Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9072.Show MeSH
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Mentions: We used a kit of minimally overlapping chromosomal deletions (a.k.a. “deficiencies”) (Table S1) to scan across the autosomes and identify genomic segments (or “hotspots”) that—when absent one copy—genetically modify PAX7-FOXO1 semilethality. Screening against ~95% of the Drosophila autosomes (~75% of the genome), we identified 33 suppressors and 28 enhancers (Table 1) (Figure 3), although three enhancers and three suppressors demonstrated P values above 0.05 and thus did not reach statistical significance. We next used smaller overlapping deletions to further delineate a subset of the hotspot regions, thereby significantly reducing candidate PAX7-FOXO1−interacting genes (Table 2). For the deficiency modifiers not submapped, candidate genes are provided in File S1.
Affiliation: Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9072.