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The Tibet chicken ( Gallus gallus ) lives on the Qinghai-Tibet Plateau and adapts to the hypoxic environment very well. The objectives of this study was to obtain candidate genes associated with hypoxia adaptation in the Tibet chicken embryos. In the present study, we used the fixation index (Fst) and cross population extended haplotype homozygosity (XPEHH) statistical methods to detect signatures of positive selection of the Tibet chicken, and analyzed the RNA sequencing data from the embryonic liver and heart with HISAT, StringTie and Ballgown for differentially expressed genes between the Tibet chicken and White leghorn ( Gallus gallus , a kind of lowland chicken) embryos hatched under hypoxia condition. Genes which were screened out by both selection signature analysis and RNA sequencing analysis could be regarded as candidate genes for hypoxia adaptation of chicken embryos. We screened out 1772 genes by XPEHH and 601 genes by Fst, and obtained 384 and 353 differentially expressed genes in embryonic liver and heart, respectively. Among these genes, 89 genes were considered as candidate genes for hypoxia adaptation in chicken embryos. ARNT, AHR, GSTK1 and FGFR1 could be considered the most important candidate genes. Our findings provide references to elucidate the molecular mechanism of hypoxia adaptation in Tibet chicken embryos.

DNA sequence variation has been widely reported as the genetic basis for adaptation, in both humans and other animals, to the hypoxic environment experienced at high altitudes. However, little is known about the patterns of gene expression underlying such hypoxic adaptations. In this study, we examined the differences in the transcriptomes of four organs (heart, kidney, liver and lung) between yak and cattle, a pair of closely related species distributed at high and low altitudes respectively. Of the four organs examined, heart shows the greatest differentiation between the two species in terms of gene expression profiles. Detailed analyses demonstrated that some genes associated with the oxygen supply system and the defense systems that respond to threats of hypoxia are differentially expressed. In addition, genes with significantly differentiated patterns of expression in all organs exhibited an unexpected uniformity of regulation along with an elevated frequency of nonsynonymous substitutions. This co-evolution of protein sequences and gene expression patterns is likely to be correlated with the optimization of the yak metabolic system to resist hypoxia., (© 2015 Stichting International Foundation for Animal Genetics.)

Objective Tibetan chickens, which have unique adaptations to extreme high-altitude environments, exhibit phenotypic and physiological characteristics that are distinct from those of lowland chickens. However, the mechanisms underlying hypoxic adaptation in the liver of chickens remain unknown. Methods RNA-sequencing (RNA-Seq) technology was used to assess the differentially expressed genes (DEGs) involved in hypoxia adaptation in highland chickens (native Tibetan chicken [HT]) and lowland chickens (Langshan chicken [LS], Beijing You chicken [BJ], Qingyuan Partridge chicken [QY], and Chahua chicken [CH]). Results A total of 352 co-DEGs were specifically screened between HT and four native lowland chicken breeds. Gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses indicated that these co-DEGs were widely involved in lipid metabolism processes, such as the peroxisome proliferator-activated receptors (PPAR) signaling pathway, fatty acid degradation, fatty acid metabolism and fatty acid biosynthesis. To further determine the relationship from the 352 co-DEGs, protein-protein interaction network was carried out and identified eight genes (ACSL1, CPT1A, ACOX1, PPARC1A, SCD, ACSBG2, ACACA, and FASN) as the potential regulating genes that are responsible for the altitude difference between the HT and other four lowland chicken breeds. Conclusion This study provides novel insights into the molecular mechanisms regulating hypoxia adaptation via lipid metabolism in Tibetan chickens and other highland animals.

As one of the most important livestock breeds on the Qinghai-Tibet Plateau, Tibetan sheep are of great importance to the local economy, agriculture and culture. Its adaptive mechanism in low temperature and low oxygen at highland altitudes has not been reported. In this study, transcriptome sequencing was used to analyze the heart, liver, spleen, lung, kidney, and muscle tissue of sheep at low and highland altitudes. LOC101112291, SELENOW, COL3A1, GPX1, TMSB4X and HSF4 were selected as candidate genes for adapting to plateau characteristics in Tibet Sheep. Besides, glutathione metabolism, arachidonic acid metabolism, nucleotide excision repair, regulation of actin cytoskeleton, protein digestion and absorption, thyroid hormone synthesis, relaxation signaling pathways may play important roles in the adaptation to plateau hypoxia, and cold tolerance. Structural analysis also showed that sequencing genes related to the adaptation mechanism of Tibet sheep to highland altitude. This study will lay a certain foundation for Tibet sheep research. Tibet sheep are an ancient species in the Qinghai Tibet Plateau. After a long period of domestication. Tibet sheep adapt to the hypoxic environment of the plateau in terms of physiology and morphology. At the same time, Tibet sheep is also one of the major sources of material for herdsmen in tibetan. In this study, six different tissue samples (heart, liver, spleen, lung, kidney, and muscle) of Tibet sheep were analyzed to reveal the underlying mechanisms of different tissues respond to hypothermia condition. The results showed that six key genes and eight important signaling pathways involved in regulating the adaptation of Tibet sheep to the plateau. In addition, there were more alternative splicing (AS) events and single nucleotide polymorphism (SNP) sites in highland altitude Tibet sheep than in lowland altitude sheep, which was also a concern in the highland altitude adaptability of Tibet sheep. [ABSTRACT FROM AUTHOR]

Subterranean rodents could maintain their normal activities in hypoxic environments underground. Eospalax fontanierii, as one kind of subterranean rodent found in China can survive very low oxygen concentration in labs. It has been demonstrated that long non-coding RNAs (lncRNAs) have important roles in gene expression regulations at different levels and some lncRNAs were found as hypoxia-regulated lncRNAs in cancers. We predicted thousands of lncRNAs in the liver and heart tissues by analyzing RNA-Seq data in Eospalax fontanierii. Those lncRNAs often have shorter lengths, lower expression levels, and lower GC contents than mRNAs. Majors of lncRNAs have expression peaks in hypoxia conditions. We found 1128 DE-lncRNAs (differential expressed lncRNAs) responding to hypoxia. To search the miRNA regulation network for lncRNAs, we predicted 471 and 92 DE-lncRNAs acting as potential miRNA target and target mimics, respectively. We also predicted the functions of DE-lncRNAs based on the co-expression networks of lncRNA-mRNA. The DE-lncRNAs participated in the functions of biological regulation, signaling, development, oxoacid metabolic process, lipid metabolic/biosynthetic process, and catalytic activity. As the first study of lncRNAs in Eospalax fontanierii, our results show that lncRNAs are popular in transcriptome widely and can participate in multiple biological processes in hypoxia responses.

Tibetan pigs are native mammalian species on the Tibetan Plateau that have evolved distinct physiological traits that allow them to tolerate high-altitude hypoxic environments. However, the genetic mechanism underlying this adaptation remains elusive. Here, based on multitissue transcriptional data from high-altitude Tibetan pigs and low-altitude Rongchang pigs, we performed a weighted correlation network analysis (WGCNA) and identified key modules related to these tissues. Complex network analysis and bioinformatics analysis were integrated to identify key genes and three-node network motifs. We found that among the six tissues (muscle, liver, heart, spleen, kidneys, and lungs), lung tissue may be the key organs for Tibetan pigs to adapt to hypoxic environment. In the lung tissue of Tibetan pigs, we identified KLF4, BCL6B, EGR1, EPAS1, SMAD6, SMAD7, KDR, ATOH8, and CCN1 genes as potential regulators of hypoxia adaption. We found that KLF4 and EGR1 genes might simultaneously regulate the BCL6B gene, forming a KLF4–EGR1–BCL6B complex. This complex, dominated by KLF4, may enhance the hypoxia tolerance of Tibetan pigs by mediating the TGF-β signaling pathway. The complex may also affect the PI3K-Akt signaling pathway, which plays an important role in angiogenesis caused by hypoxia. Therefore, we postulate that the KLF4–EGR1–BCL6B complex may be beneficial for Tibetan pigs to survive better in the hypoxia environments. Although further molecular experiments and independent large-scale studies are needed to verify our findings, these findings may provide new details of the regulatory architecture of hypoxia-adaptive genes and are valuable for understanding the genetic mechanism of hypoxic adaptation in mammals.

Hypoxia can induce cell damage, inflammation, carcinogenesis, and inhibit liver regeneration in non-adapted species. Because of their excellent hypoxia adaptation features, subterranean rodents have been widely studied to clarify the mechanism of hypoxia adaptation. Eospalax fontanierii, which is a subterranean rodent found in China, can survive for more than 10 h under 4% O2 without observable injury, while Sprague-Dawley rats can survive for less than 6 h under the same conditions. To explore the potential mechanism of hypoxia responses in E. fontanierii, we performed RNA-seq analysis of the liver in E. fontanierii exposed to different oxygen levels (6.5% 6h, 10.5% 44h, and 21%). Based on the bioinformatics analysis, 39,439 unigenes were assembled, and 56.78% unigenes were annotated using public databases (Nr, GO, Swiss-Prot, KEGG, and Pfam). In total, 725 differentially expressed genes (DEGs) were identified in the response to hypoxia; six with important functions were validated by qPCR. Those DEGs were mainly involved in processes related to lipid metabolism, steroid catabolism, glycolysis/gluconeogenesis, and the AMPK and PPAR signaling pathway. By analyzing the expression patterns of important genes related to energy associated metabolism under hypoxia, we found that fatty acid oxidation and gluconeogenesis were increased, while protein synthesis and fatty acid synthesis were decreased. Furthermore, the upregulated expression of specific genes with anti-apoptosis or anti-oxidation functions under hypoxia may contribute to the mechanism by which E. fontanierii tolerates hypoxia. Our results provide an understanding of the response to hypoxia in E. fontanierii, and have potential value for biomedical studies.

Tibetan pigs are native mammalian species on the Tibetan Plateau that have evolved distinct physiological traits that allow them to tolerate high-altitude hypoxic environments. However, the genetic mechanism underlying this adaptation remains elusive. Here, based on multitissue transcriptional data from high-altitude Tibetan pigs and low-altitude Rongchang pigs, we performed a weighted correlation network analysis (WGCNA) and identified key modules related to these tissues. Complex network analysis and bioinformatics analysis were integrated to identify key genes and three-node network motifs. We found that among the six tissues (muscle, liver, heart, spleen, kidneys, and lungs), lung tissue may be the key organs for Tibetan pigs to adapt to hypoxic environment. In the lung tissue of Tibetan pigs, we identified KLF4 , BCL6B , EGR1 , EPAS1 , SMAD6 , SMAD7 , KDR , ATOH8 , and CCN1 genes as potential regulators of hypoxia adaption. We found that KLF4 and EGR1 genes might simultaneously regulate the BCL6B gene, forming a KLF4–EGR1–BCL6B complex. This complex, dominated by KLF4 , may enhance the hypoxia tolerance of Tibetan pigs by mediating the TGF-β signaling pathway. The complex may also affect the PI3K-Akt signaling pathway, which plays an important role in angiogenesis caused by hypoxia. Therefore, we postulate that the KLF4–EGR1–BCL6B complex may be beneficial for Tibetan pigs to survive better in the hypoxia environments. Although further molecular experiments and independent large-scale studies are needed to verify our findings, these findings may provide new details of the regulatory architecture of hypoxia-adaptive genes and are valuable for understanding the genetic mechanism of hypoxic adaptation in mammals. [ABSTRACT FROM AUTHOR]