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Expression Profiling of Spalax ehrenbergi: bioprospecting for hypoxia tolerance

ABSTRACT: This study compares response to hypoxia in muscle between 2 hypoxia tolerant species of Spalax ehrenbergi, blind subterranean mole rat . The blind subterranean mole rat (Spalax ehrenbergi superspecies) is an excellent model of hypoxic tolerance, living underground and exposed to fluctuating O2 and CO2 levels. Unique structural and functional adaptations of the cardiovascular and respiratory systems allow survival at severely reduced oxygen tension. In this study we have compared expression profiles of muscle tissue between two hypoxia tolerant species of Spalax ehrengergi at normoxic (21%) and hypoxic (3%) levels of oxygen concentration by cross species hybridization using a mouse cDNA array containing 15,000 gene elements. Results uncover numerous genes involved in angiogenesis, apoptosis, and oxidative stress and responding in a species specific manner to hypoxia. Among the most striking, cardiac ankyrin repeat protein (Carp) and activating transcription factor 3 (Atf3), LIM and cysteine-rich domains 1 (Lmcd1) and syndecan 2 (Sdc2). These results support the hypothesis that Spalax is variably adapted to fluctuating oxygen tension. Differences may involve very specific metabolic pathways and functional adaptations at the structural and molecular levels. Elucidation of the natural variation and evolutionary changes under hypoxia within this superspecies may have biomedical applications in ischemic syndromes and cancer. Keywords: hypoxia, Spalax, cDNA microarray

OTHER RELATED OMICS DATASETS IN: PRJNA93939

ORGANISM(S): Mus musculus Nannospalax judaei Nannospalax ehrenbergi Nannospalax galili

PROVIDER: GSE3763 | GEO | 2006/07/14

SECONDARY ACCESSION(S): PRJNA93939

REPOSITORIES: GEO

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Project description:Background: Spalax, the blind mole rat, developed an extraordinary cancer resistance during 40 million years of evolution in a subterranean, hypoxic, thus DNA damaging, habitat. In 50 years of Spalax research, no spontaneous cancer development has been observed. The mechanisms underlying this resistance are still not clarified. We investigated the genetic difference between Spalax and mice that might enable the Spalax relative resistance to cancer development. We compared Spalax and mice responses to a treatment with the carcinogen 3-Methylcholantrene, as a model to assess Spalax’ cancer-resistance. Results: We compared RNA-Seq data of untreated Spalax to Spalax with a tumor and identified a high number of differentially expressed genes. We filtered these genes by their expression in tolerant Spalax that resisted the 3MCA, and in mice, and found 25 genes with a consistent expression pattern in the samples susceptible to cancer among species. Contrasting the expressed genes in Spalax with benign granulomas to those in Spalax with malignant fibrosarcomas elucidated significant differences in several pathways, mainly the extracellular matrix and the immune system. We found a central cluster of ECM genes that differ greatly between conditions. Further analysis of these genes revealed potential drug targets and associated microRNAs. We also show that in Spalax has higher levels of gene expression of some DNA repair pathways than other murines, like the majority of Fanconi Anemia pathway. Conclusion: The comparison of the treated with the untreated tissue revealed a regulatory complex that might give an answer how Spalax is able to restrict the tumor growth. By strengthening the extracellular matrix, the possible growth is limited, and the proliferation of cancer cells was prevented. We hypothesize that this regulatory cluster plays a major role in the cancer resistance of Spalax. Furthermore, we identified 25 additional candidate genes that show a distinct expression pattern in untreated or tolerant Spalax compared to animals that developed a growth, either benign or malignant. While further study is necessary, we believe that these genes may be used as markers in cancer detection.

Project description:Background: Spalax, the blind mole rat, developed an extraordinary cancer resistance during 40 million years of evolution in a subterranean, hypoxic, thus DNA damaging, habitat. In 50 years of Spalax research, no spontaneous cancer development has been observed. The mechanisms underlying this resistance are still not clarified. We investigated the genetic difference between Spalax and mice that might enable the Spalax relative resistance to cancer development. We compared Spalax and mice responses to a treatment with the carcinogen 3-Methylcholantrene, as a model to assess Spalax’ cancer-resistance. Results: We compared RNA-Seq data of untreated Spalax to Spalax with a tumor and identified a high number of differentially expressed genes. We filtered these genes by their expression in tolerant Spalax that resisted the 3MCA, and in mice, and found 25 genes with a consistent expression pattern in the samples susceptible to cancer among species. Contrasting the expressed genes in Spalax with benign granulomas to those in Spalax with malignant fibrosarcomas elucidated significant differences in several pathways, mainly the extracellular matrix and the immune system. We found a central cluster of ECM genes that differ greatly between conditions. Further analysis of these genes revealed potential drug targets and associated microRNAs.We also show that in Spalax has higher levels of gene expression of some DNA repair pathways than other murines, like the majority of Fanconi Anemia pathway. Conclusion: The comparison of the treated with the untreated tissue revealed a regulatory complex that might give an answer how Spalax is able to restrict the tumor growth. By strengthening the extracellular matrix, the possible growth is limited, and the proliferation of cancer cells was prevented. We hypothesize that this regulatory cluster plays a major role in the cancer resistance of Spalax. Furthermore, we identified 25 additional candidate genes that show a distinct expression pattern in untreated or tolerant Spalax compared to animals that developed a growth, either benign or malignant. While further study is necessary, we believe that these genes may be used as markers in cancer detection.

Project description:Changes in gene regulation have long been though to underlie most phenotypic differences between species. Subterranean rodents, and in particular the naked mole-rat (NMR), have attracted substantial attention due to their proposed phenotypic adaptations, which include hypoxia tolerance, metabolic changes and cancer resistance. However, it is largely unknown what regulatory changes may associate with these phenotypic traits, and whether these are unique to the NMR, the mole-rat clade or also present in other mammals. Here, we undertook a comparative genomics approach to identify genome-wide promoter and enhancer regions harbouring epigenomic hallmarks of regulatory activity, in heart and liver from two mole-rat species (NMR and DMR) and two rodent outgroups. To identify promoters and enhancers displaying robust shifts in regulatory activity in the mole-rat clade, we adapted and applied a phylogenetic modeling approach to quantitatively compare epigenomic signals at orthologous locations, while accounting for phylogenetic distance and inter-species variation. This method identified thousands of orthologous promoter and enhancer regions with increased activity in ancestral or single-species mole-rat branches, as well as hundreds of promoters and enhancers with reduced activity in mole-rats versus other rodents. These elements underlie both shared tissue-specific changes in gene regulation associated with mole-rat evolution, which include metabolic and functional adaptations in heart and liver. Moreover, by comparing mole-rat specific changes in promoters and enhancers between ancestral and single-species branches, our data revealed a number of candidate pathways with stepwise regulatory changes during mole-rat evolution. Lastly, we analysed the genomic properties of non-alignable promoters and enhancers in mole-rats, and report (i) their overlap with specific repetitive elements and transcription factor binding sites; and (ii) their association with metabolic gene functions. On the whole, these comparative analyses reveal mole-rat specific epigenomic changes across orthologous and non-mappable promoters and enhancers - which inform previously reported mole-rat adaptations from a gene regulation perspective.

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Expression Profiling of Spalax ehrenbergi: bioprospecting for hypoxia tolerance

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