Myc-regulated miRNAs modulate p53 expression in Drosophila.

GERVE PAULA; DEKANTY ANDRES

Congreso; 63 Annual Drosophila Research Conference; 2022

Genetic Society of America

Myc, a conserved transcription factor involved in the regulation of growth and metabolism, has been shown to regulatethe biogenesis of miRNAs in cultured mammalian cells, however, the exact mechanisms by which Myc affects miRNAfunction remain unclear. Here we provide evidences that Myc directly regulates the expression of a high number ofmiRNAs in Drosophila. ChIP-seq analysis revealed that dMyc is highly enriched in the promoter region of 113 (50%)miRNA genes, and dMyc depletion showed reduced expression of most miRNA genes analysed. Along with reducedpri-miRNA expression, we observed decreased levels of pre- and mature miRNAs and increased expression of miRNAactivity sensors (miR-GFP) in myc-depleted cells. Conversely, Myc overexpression increased miRNA levels and reducedmiR-GFP expression, strongly suggesting that dMyc modulates the expression and processing of miRNAs. We also showthat Myc-dependent regulation of miRNA biogenesis plays a critical role in the response to nutrient stress. Dmp53, thesingle Drosophila ortholog of mammalian p53, is negatively regulated by miR-305 in the fat body in a nutrient-dependentmanner, and its activation is required for maintaining metabolic homeostasis and promoting survival under nutrientdeprivation. Our results revealed that dMyc directly binds miR-305 locus and promotes its expression, thus maintaininglow Dmp53 levels in the fat body of well-fed animals. Under starvation conditions, however, dMyc protein levels andmiR-305 expression are reduced which result in increased Dmp53 levels. These findings demonstrate an essential role forMyc in regulating miRNA expression and highlight the importance of Myc-dependent regulation of miRNA biogenesis in metabolic homeostasis and organismal survival upon nutrient stress