MIR-274 IS A NEW PLAYER IN THE REGULATION OF HIF-DEPENDENT HYPOXIA RESPONSE IN DROSOPHILA

DE LELLA EZCURRA, ANA; SORIANELLO, ELEONORA; MELANI, MARIANA; SANTILLAN, EMILIO; WAPPNER, PABLO

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

10 Sociedades Científicas de Argentina

When oxygen levels descend, metazoans generate a complex physiological response in order to restore homeostasis. In mammals, the main regulator of this response is the heterodimeric transcription factor HIF-1 (Hypoxia Inducible Factor 1). At normoxia, the HIF-1α subunit is hydroxylated by specific prolyl hydroxylase domain proteins (PHDs), which use oxygen as substrate. The hydroxylation leads to ubiquitination and proteasomal degradation of HIF-1α. In hypoxia, the activity of the PHDs is inhibited and HIF-1α is not hydroxylated. This leads to stabilization and accumulation of HIF-1α, dimerization with HIF-1β, and translocation of the dimer to the nucleus where induces the transcription of its target genes. Given this adaptive response is extremely well conserved, we use Drosophila to uncover new regulatory mechanisms. We have established that the microRNA processing machinery plays a central role in the regulation of HIF-dependent response, and we identified four miRNAs whose overexpression increases the transcription of a HIF-dependent reporter. We are characterizing the function of one of those microRNAs, mir-274, in relation with the adaptation to hypoxia and its possible regulatory function of HIF. We have observed that both the overexpression and loss of function of miR-274 is sufficient to induce changes in the expression of a HIF transcriptional reporter, compared to control embryos (p