Transcriptome analysis of the spalax hypoxia survival response includes suppression of apoptosis and tight control of angiogenesis

Abstract

BackgroundThe development of complex responses to hypoxia has played a key role in the evolution of mammals, as inadequate response to this condition is frequently associated with cardiovascular diseases, developmental disorders, and cancers. Though numerous studies have used mice and rats in order to explore mechanisms that contribute to hypoxia tolerance, these studies are limited due to the high sensitivity of most rodents to severe hypoxia. The blind subterranean mole rat Spalax is a hypoxia tolerant rodent, which exhibits unique longevity and therefore has invaluable potential in hypoxia and cancer research.ResultsUsing microarrays, transcript abundance was measured in brain and muscle tissues from Spalax and rat individuals exposed to acute and chronic hypoxia for varying durations. We found that Spalax global gene expression response to hypoxia differs from that of rat and is characterized by the activation of functional groups of genes that have not been strongly associated with the response to hypoxia in hypoxia sensitive mammals. Using functional enrichment analysis of Spalax hypoxia induced genes we found highly significant overrepresentation of groups of genes involved in anti apoptosis, cancer, embryonic/sexual development, epidermal growth factor receptor binding, coordinated suppression and activation of distinct groups of transcription factors and membrane receptors, in addition to angiogenic related processes. We also detected hypoxia induced increases of different critical Spalax hub gene transcripts, including antiangiogenic genes associated with cancer tolerance in Down syndrome human individuals.ConclusionsThis is the most comprehensive study of Spalax large scale gene expression response to hypoxia to date, and the first to use custom Spalax microarrays. Our work presents novel patterns that may underlie mechanisms with critical importance to the evolution of hypoxia tolerance, with special relevance to medical research.

Genome maintenance and bioenergetics of the long-lived hypoxia-tolerant and cancer-resistant blind mole rat, Spalax: a cross-species analysis of brain transcriptome

“…S3). In a previous RNA-Seq Spalax brain microarray study22, these ECM related terms were significantly overrepresented among hypoxia responsive genes, and were part of a cluster of functionally-related terms associated with hypoxia-induced angiogenesis.…”

“…The Spalax genome was recently sequenced21, and Spalax normoxia vs. hypoxia genome-wide molecular responses were explored in both brain and muscle tissues2122. These studies revealed the involvement of multiple functional groups of genes in the hypoxia-induced responses of Spalax .…”

“…These studies revealed the involvement of multiple functional groups of genes in the hypoxia-induced responses of Spalax . For example, it was shown that hypoxia induces genome-wide change in transcript abundance of a remarkably large number of genes associated with apoptotic regulation, including anti-apoptotic response and cancer-related genes, in Spalax brain and muscle tissues22. In cells with intact p53, hypoxia-related conditions may lead to the activation of apoptosis14.…”

Pronounced cancer resistance in a subterranean rodent, the blind mole-rat, Spalax: in vivo and in vitroevidence

“…Noteworthy are VEGF , constitutively highly expressed as compared to rats [7]; p53 that harbors substitutions in the DNA-binding site, identical to the most common p53 mutations in tumors; however, in Spalax it renders a bias against apoptosis but favors cell cycle arrest/DNA repair both in vitro and in vivo [8]; and a unique Spalax heparanase splice variant that was shown to decrease tumor size in mice by a factor of 7 and reduce metastatic activity compared to native mice heparanase [9]. Furthermore, assessment of Spalax transcriptome assembly and expression data has revealed enrichment of genes that overlap cancer resistance, apoptosis, angiogenesis pathways and hypoxia-tolerance [10,11]. This suggests that Spalax is potentially resistant to malignant transformation.…”

HIF-1α-induced β-catenin activation prevents prion-mediated neurotoxicity

“…Hypoxic conditions regulate gene transcription in cellular responses to promote metabolism and angiogenesis through adaptive processes (13)(14)(15)(16). Accordingly, modulation of gene transcription through HIF-1 plays an important role in hypoxia for cell survival (17)(18)(19)(20)(21)(22).…”