Adaptation of theSpalax galilitranscriptome to life under hypoxia may hold a key to a complex phenotype including longevity and cancer resistance

Abstract

AbstractThe muroid rodentNannospalax galili(syn.Spalax) is adapted to life in underground burrows and tolerates acute exposure to severe hypoxia. Adaptation to hypoxia is correlated with delayed onset of ageing and resistance against tumour formation.Spalaxbecomes five to seven times older than its relatives, the mouse and rat, without displaying signs of ageing or developing ageing-related disorders like cancer. Investigating and understanding adapted genes and gene regulatory networks ofSpalaxmight pinpoint novel strategies to maintain an extended healthy phenotype in humans. Here we analysed and compared RNA-Seq data of liver, kidney and spleen ofSpalaxand rat subjected to 6% O2or normoxia. We identified differentially expressed genes and pathways common to multiple organs inSpalaxand rat. Body-wide differences betweenSpalaxand rat affected biological processes like cell death, defence against reactive oxygen species (ROS), DNA repair, energy metabolism, immune response and angiogenesis, which altogether might play a crucial role inSpalax’s adaptation to life under oxygen deprivation. In all organs, mRNA expression of genes associated with genome stability maintenance and DNA repair was elevated inSpalaxcompared to rat, accompanied by a lower gene expression of genes associated with aerobic energy metabolism and proinflammatory processes. These transcriptomic changes might be accountable for the extraordinary lifespan ofSpalaxand its cancer resistance. Our results reveal gene regulatory networks that become candidates for the investigation of the molecular bases that underlie the complex phenotype ofSpalax.