A global transgenic RNAi screen identifies transcription factors that modulate myofiber size in Drosophila.

Myofiber atrophy occurs with aging and in many diseases but the underlying mechanisms are incompletely understood. Here, we have used >1,100 muscle-targeted RNAi interventions to comprehensively assess the function of 447 transcription factors in the developmental growth of body wall skeletal muscles in Drosophila. This screen identifies new regulators of myofiber atrophy and hypertrophy, including the transcription factor Deaf1. Deaf1 RNAi increases myofiber size whereas Deaf1 overexpression induces atrophy. Consistent with its annotation as a Gsk3 phosphorylation substrate, Deaf1 and Gsk3 induce largely overlapping transcriptional changes that are opposed by Deaf1 RNAi. The top category of Deaf1-regulated genes consists of glycolytic enzymes, which are suppressed by Deaf1 and Gsk3 but are upregulated by Deaf1 RNAi. Similar to Deaf1 and Gsk3 overexpression, RNAi for glycolytic enzymes reduces myofiber growth. Altogether, this study defines the repertoire of transcription factors that regulate developmental myofiber growth and the role of Gsk3/Deaf1/glycolysis in this process. RNA-sequencing data from Drosophila body wall skeletal muscles (n=3/genotype) with the following genotypes: Mef2>whiteRNAi(BL#33623) [control RNAi] Mef2>Deaf1RNAi(BL#32512) [muscle-specific Deaf1 RNAi] Mef2>+ [control, no transgene] Mef2>Deaf1 [muscle-specific Deaf1 overexpression] Mef2>Gsk3CA(BL#5255). [muscle-specific Gsk3 overexpression]