View Program - 63rd Annual Drosophila Research Conference

The rapid growth that occurs during Drosophila larvae requires a dramatic rewiring of central carbon metabolism to support biosynthesis. Previous studies in our lab demonstrated that this exponential growth phase is preceded by a dramatic metabolic switch, which results in the transcriptional up-regulation of genes involved in carbohydrate metabolism, including those that encode enzymes involved in glycolysis and the pentose phosphate pathway as well as Lactate Dehydrogenase. The resulting metabolic program exhibits the hallmark characteristics of aerobic glycolysis and establishes a physiological state that supports biomass accumulation similar to that seen in tumor cells. Studies in the fly have so far have only discovered a single transcription factor involved in this process - the DrosophilaEstrogen-Related Receptor (dERR), which is absolutely required to up-regulated carbohydrate metabolism in preparation for larval growth. Here we describe our discovery that Sima, the sole Drosophila ortholog of the hypoxia inducible factor-1 alpha (Hif1-a), is also essential for promoting aerobic glycolysis in larvae. Using CRISPR/CAS9 generated sima alleles that disrupt an exon shared among all isoforms, we discovered that the classic sima p-element insertion mutation sima ^kG07607 represents a weak hypomorph that exhibits very mild metabolic defects. In contrast to this canonical allele, our novel null mutations exhibit a mid-L2 lethal phase and phenocopy the metabolic defects observed in dERR mutants. Moreover, transcriptomic analysis of sima mutants reveal a dramatic downregulation in glycolytic genes, with the overall transcriptional profile mimicking that of the dERR mutant. Subsequent metabolomics studies revealed that, when compared to control larvae, sima trans-heterozygous mutants exhibit >90% decrease in lactate and 2-HG and a two-fold increase in the circulating disaccharide trehalose. Altogether, these preliminary studies indicate that sima, like dERR, is an essential regulator of the larval metabolic program – a result supported by previous findings that Sima can physically bind dERR. Our future studies will examine the interaction between Sima and dERR to understand how these two evolutionarily conserved transcription factors control aerobic glycolysis in the context of both normal animal development and cancer metabolism.

The Drosophila gene sima is an essential regulator of the larval glycolytic program

**The Drosophila gene sima is an essential regulator of the larval glycolytic program**