Myc-regulated miRNAs modulate p53 expression in Drosophila.
Authors: Gervé María Paula; Sanchez Juan; Ingaramo Clara; Dekanty Andres
Affiliation: IAL (instituto de agrobiotecnologia del Litoral)
Keywords: q. miRNA; f. dietary restriction/fasting
Myc, a conserved transcription factor involved in the regulation of growth and metabolism, has been shown to regulate the biogenesis of miRNAs in cultured mammalian cells, however, the exact mechanisms by which Myc affects miRNA function remain unclear. Here we provide evidences that Myc directly regulates the expression of a high number of miRNAs 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 reduced pri-miRNA expression, we observed decreased levels of pre- and mature miRNAs and increased expression of miRNA activity sensors (miR-GFP) in myc-depleted cells. Conversely, Myc overexpression increased miRNA levels and reduced miR-GFP expression, strongly suggesting that dMyc modulates the expression and processing of miRNAs. We also show 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 fat body in a nutrient-dependent manner, and its activation is required for maintaining metabolic homeostasis and promoting survival under nutrient deprivation. Our results revealed that dMyc 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, dMyc 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.