Myc-REGULATED miRNAs MODULATE P53 EXPRESSION IN Drosophila

SANCHEZ JUAN; INGARAMO MARIA CLARA; GERVÉ PAULA; DEKANTY ANDRES

online

Congreso; 63rd Annual Drosophila Research Conference; 2022

Myc is a conserved transcription factor involved in the regulation of growth and metabolism. Previous studies in mammalian cells have reported that Myc is able to regulate the biogenesis of microRNAs (miRNAs), short 20-22 nucleotide RNA molecules that regulate gene expression. However, the exact mechanisms by which Myc affects miRNA biogenesis and/or activity remain unclear. By combining ChIP-seq data, bioinformatics analysis and qRT-PCR we showed that Drosophila Myc binds directly to 113 miRNA genes, positively regulating their transcription. Myc depletion in Drosophila larvae showed reduced levels of miRNAs and increased expression of miRNA activity sensors (miR-GFP). Conversely, Myc overexpression increased miRNA levels and reduced miR-GFP expression. We have also shown that Myc-dependent regulation of miRNA biogenesis plays a critical role in the response to nutrient stress. Dmp53, the single Drosophila ortholog of mammalian p53, is negatively regulated by miR-305 in the Drosophila adipose tissue (fat body). Dmp53 activation in the fat body is required for maintaining metabolic homeostasis and promoting animal survival under nutrient deprivation. Here we showed that Myc directly binds miR-305 locus and promotes its expression, thus maintaining low Dmp53 levels in the fat body of well-fed animals. Under starvation conditions, however, Myc protein levels and miR-305 expression are reduced which result in increased Dmp53 levels. These findings demonstrate an essential role for Myc in regulating miRNA expression and highlight the importance of Myc-dependent regulation of miRNA biogenesis in metabolic homeostasis and organismal survival upon nutrient stress.