Myc sustains Regional and Sex-biased Organ Zonation in the Drosophila Intestine

Organs exhibit distinct transcriptional and metabolic territories; how and why such organ zonation differs between the sexes is unclear. Using adult Drosophila intestines, we combine whole-organ 3D cellular mapping with metabolic profiling to uncover regional differences in enterocyte ploidy and metabolism that vary by sex and genotype. Zonation emerges from opposing, region-specific and sex-biased actions of the sex determinant Doublesex (Dsx) and the transcription factor Myc. In enterocytes, male-specific Dsx represses Myc, resulting in female-biased Myc expression. Myc, in turn, increases enterocyte ploidy, rendering it both female-biased and regional. Myc also sustains a female-specific lipid profile, marked by sexbiased expression of a cluster of lipases and selective triacylglycerol storage in the anterior midgut. Myc activity in female enterocytes sustains peripheral lipid reserves and fecundity. These findings identify relevant roles for Myc in sex differentiation and the intestine as a key, previously overlooked contributor to sex differences in lipid metabolism.