Cellular adaptations to hypoxia. Novel mechanisms of HIF regulation

PABLO WAPPNER

Barcelona

Congreso; Leloir Lecture, Sociedad Española de Bioquímica y Biologia Molecular; 2017

FEBS: Sociedad Española de Bioquímica y Biologia Molecular

Cells and whole organisms adapt to low oxygen conditions (hypoxia) through specific modifications in their transcription and translation profiles. The Hypoxia Inducible Factor (HIF), a transcription factor conserved in all animal phyla, plays a central role in this adaptation. We have carried out genetic screens in Drosophila melanogaster to define mechanisms that mediate survival in hypoxia. An RNAi based genome-wide screen performed in Drosophila S2 cells rendered 21 novel regulators of HIF, including Argonaute1 and other components of the miRNA machinery. An over-expression screen of all the miRNAs encoded in the Drosophila genome, carried-out in vivo in transgenic fly lines, led to the identification of miR-190 that mediates inhibition of negative regulators of HIF, thereby enhancing molecular and biological responses to hypoxia. Other HIF novel regulators were the chromatin modifying complex TIP60, which is recruited by HIF to hypoxia-inducible promoters and is required for RNA Pol II dependent elongation, and the translational repressor Musashi that regulates translation of HIF in an oxygen-dependent manner. Thus, cell adaptation to hypoxia is controlled by a complex array of transcriptional and translational mechanisms that operate at different levels.