Abstract
ABSTRACTThe naked mole rat (NMR; Heterocephalus glaber) is a small rodent species found in regions of Kenya, Ethiopia and Somalia. It has a high tolerance for hypoxia and is thus considered one of the most important natural models for studying hypoxia tolerance mechanisms. The various mechanisms underlying the NMR's hypoxia tolerance are beginning to be understood at different levels of organization, and next-generation sequencing methods promise to expand this understanding to the level of gene expression. In this study, we examined the sequence and transcript abundance data of the muscle transcriptome of NMRs exposed to hypoxia using the Illumina HiSeq 2500 system to clarify the possible genomic adaptive responses to the hypoxic underground surroundings. The RNA-seq raw FastQ data were mapped against the NMR genome. We identified 2337 differentially expressed genes (DEGs) by comparison of the hypoxic and control groups. Functional annotation of the DEGs by gene ontology (GO) analysis revealed enrichment of hypoxia stress-related GO categories, including ‘biological regulation’, ‘cellular process’, ‘ion transport’ and ‘cell-cell signaling’. Enrichment of DEGs in signaling pathways was analyzed against the Kyoto Encyclopedia of Genes and Genomes (KEGG) database to identify possible interactions between DEGs. The results revealed significant enrichment of DEGs in focal adhesion, the mitogen-activated protein kinase (MAPK) signaling pathway and the glycine, serine and threonine metabolism pathway. Furthermore, inhibition of DEGs (STMN1, MAPK8IP1 and MAPK10) expression induced apoptosis and arrested cell growth in NMR fibroblasts following hypoxia. Thus, this global transcriptome analysis of NMRs can provide an important genetic resource for the study of hypoxia tolerance in mammals. Furthermore, the identified DEGs may provide important molecular targets for biomedical research into therapeutic strategies for stroke and cardiovascular diseases.
Highlights
Hypoxia is a serious challenge for aerobic organisms, which depend on aerobic oxidation of glucose for respiration and energy production in the mitochondria (Hayashi, 1968; Savin, 1966)
RNA-seq and differentially expressed genes (DEGs) To characterize the transcriptomic responses of naked mole rat (NMR) to hypoxic stress, 10 cDNA libraries were constructed from both hypoxiastressed muscle tissue and control muscle tissue
Our analysis indicated that DEGs were enriched in signaling pathways related to focal adhesion, mitogen-activated protein kinase (MAPK) signaling pathway, dilated cardiomyopathy, circadian rhythm-mammal, cell cycle, and glycine, serine and threonine metabolism and metabolic pathways, which is consistent with the results of the Gene Ontology (GO) analysis
Summary
Hypoxia is a serious challenge for aerobic organisms, which depend on aerobic oxidation of glucose for respiration and energy production in the mitochondria (Hayashi, 1968; Savin, 1966). A better understanding of the mechanisms responsible for hypoxia tolerance in vertebrates is crucial for the prevention and therapy of ischemic diseases, and for developing protective measures against hypoxic environments. The changes in many pathways, including hypoxia-inducible pathways and hypoxia-protective pathways resulting from hypoxic stress responses in mammalian cells, play an important role in ion homeostasis, reactive oxygen species scavenging, and cell growth and apoptosis. Mitogen-activated protein kinases (MAPKs) are a class of serine/threonine protein kinases which control cell growth, differentiation, pathological processes, and a variety of important cellular physiological adaptation to environmental stress (e.g. hypoxia). Comprehensive investigations of the transcriptomes of some unique hypoxia-tolerant species are necessary to gain a better understanding of the genetic mechanisms responsible for hypoxia tolerance
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