KLF4, a Key Regulator of a Transitive Triplet, Acts on the TGF-β Signaling Pathway and Contributes to High-Altitude Adaptation of Tibetan Pigs

2020 ◽  
Author(s):  
Tao Wang ◽  
Yuanyuan Guo ◽  
Shengwei Liu ◽  
Chaoxin Zhang ◽  
Tongyan Cui ◽  
...  
Keyword(s):  
Network Analysis ◽  
High Altitude ◽  
Signaling Pathway ◽  
Mammalian Species ◽  
The Tibetan Plateau ◽  
Tibetan Pigs ◽  
Regulatory Architecture ◽  
Hypoxia Adaptation ◽  
Suitable Animal Model ◽  
Transcriptional Changes

Abstract Background: 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. They can be used as a suitable animal model for exploring the molecular mechanism of hypoxia adaptation in high-altitude organisms.Results: Here, based on multi-tissue 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 size-3 network motifs. The results showed that compared to other tissues, the lungs of Tibetan pigs and Rongchang pigs are more significantly different, showing more adaptive transcriptional changes. In the lung tissues 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 simultaneously regulate the BCL6B gene, forming a KLF4-EGR1-BCL6B transitive triplet. This transitive triplet, dominated by KLF4, may enhance the hypoxia adaptability of Tibetan pigs by mediating the TGF-β signaling pathway. This triplet also regulates the KDR gene, which is involved in the PI3K-Akt signaling pathway and plays an important role in hypoxia adaptation. Conclusions: We postulate that the KLF4-EGR1-BCL6B transitive triplet may contribute to the adaptation of Tibetan pigs to hypoxic environments. These findings provide new details of the regulatory architecture of hypoxia-adaptive genes and are valuable for understanding the genetic mechanism of hypoxic adaptation in mammals.

scholarly journals KLF4, a Key Regulator of a Transitive Triplet, Acts on the TGF-β Signaling Pathway and Contributes to High-Altitude Adaptation of Tibetan Pigs

2021 ◽  
Vol 12 ◽  
Author(s):  
Tao Wang ◽  
Yuanyuan Guo ◽  
Shengwei Liu ◽  
Chaoxin Zhang ◽  
Tongyan Cui ◽  
...  
Keyword(s):  
Network Analysis ◽  
High Altitude ◽  
Signaling Pathway ◽  
Lung Tissue ◽  
Large Scale ◽  
Mammalian Species ◽  
Hypoxia Tolerance ◽  
Genetic Mechanism ◽  
The Tibetan Plateau ◽  
Tibetan Pigs

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.

scholarly journals Network Biology led identification of critical miRNA modules for High Altitude hypoxia and their potential as dietary supplements

2021 ◽  
Author(s):  
Apoorv Gupta ◽  
Sugadev R ◽  
Y K Sharma ◽  
Pankaj Khurana
Keyword(s):  
Network Analysis ◽  
High Altitude ◽  
Regulatory Networks ◽  
Sequence Similarity ◽  
Functional Module ◽  
Mammalian Species ◽  
Differentially Expressed ◽  
Mammalian Host ◽  
High Altitudes ◽  
Tf Gene

Abstract Early ascent to high altitude can cause severe damage to body functions and may lead to many fatal high-altitude disorders. To cope up with such conditions, the human body undergoes physiological and biochemical changes in order to adapt to extreme environmental conditions at high altitudes. Several microRNAs (miRNAs), Transcription Factors (TFs), and genes have been studied separately for their role in early adaptive molecular responses. We hypothesize that network analysis of miRNA-TF-gene co-regulatory networks of circulatory miRNAs (CmiRNAs) which are differentially expressed at high altitudes could reveal a complex regulatory functional module that might be controlling molecular adaptive responses at high altitude. A comprehensive and non-redundant list of differentially expressed human CmiRNAs during high altitude ascent was collated and 470 Feed-Forward Loops (FFLs) tripartite motifs were identified in the miRNA-TF-gene co-regulatory networks. Network analysis and K-means clustering identified 11 biologically overrepresented FFLs regulated by 8 miRNAs hsa-miR-335-5p, hsa-miR-26a-1-3p, hsa-miR-210-3p, hsa-miR-193b-3p, hsa-miR-17-5p, hsa-miR-16-5p, hsa-miR-5582-5p and hsa-miR-130a-3p. Pathway enrichment identified metabolism and inflammation as important hallmark responses responsible for high altitude adaptation. These miRNAs were evaluated for their supplementation from dietary sources. Phylogenetic analysis with 4 other mammalian and non-mammalian species showed that Bos taurus (cattle) milk could be a possible source of these dietary miRNAs. Exogenous miRNAs bta-mir-16-1, bta-mir-130a, bta-miR-335, and bta-miR-210 have >95% of sequence similarity and could become potential dietary miRNAs candidates. The sequence, structural properties, and high AGO2 binding efficiency of all these exogenous miRNAs show good serum stability and cellular uptake possibility in the mammalian host. Bta-miR-210 with highest Minimal Folding free Energy Index (MFEI) and highest Atomic Contact Energy (ACE) with AGO2 has the best potential to be a dietary supplement.

scholarly journals Microarray analysis reveals an inflammatory transcriptomic signature in peripheral blood for sciatica

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yi Wang ◽  
Guogang Dai ◽  
Ling Jiang ◽  
Shichuan Liao ◽  
Jiao Xia
Keyword(s):  
Functional Analysis ◽  
Network Analysis ◽  
Peripheral Blood ◽  
Differentially Expressed ◽  
Healthy Controls ◽  
Toll Like Receptor ◽  
Qrt Pcr ◽  
Transcriptomic Signature ◽  
Transcriptional Changes ◽  
Key Genes

Abstract Background Although the pathology of sciatica has been studied extensively, the transcriptional changes in the peripheral blood caused by sciatica have not been characterized. This study aimed to characterize the peripheral blood transcriptomic signature for sciatica. Methods We used a microarray to identify differentially expressed genes in the peripheral blood of patients with sciatica compared with that of healthy controls, performed a functional analysis to reveal the peripheral blood transcriptomic signature for sciatica, and conducted a network analysis to identify key genes that contribute to the observed transcriptional changes. The expression levels of these key genes were assessed by qRT-PCR. Results We found that 153 genes were differentially expressed in the peripheral blood of patients with sciatica compared with that of healthy controls, and 131 and 22 of these were upregulated and downregulated, respectively. A functional analysis revealed that these differentially expressed genes (DEGs) were strongly enriched for the inflammatory response or immunity. The network analysis revealed that a group of genes, most of which are related to the inflammatory response, played a key role in the dysregulation of these DEGs. These key genes are Toll-like receptor 4, matrix metallopeptidase 9, myeloperoxidase, cathelicidin antimicrobial peptide, resistin and Toll-like receptor 5, and a qRT-PCR analysis validated the higher transcript levels of these key genes in the peripheral blood of patients with sciatica than in that of healthy controls. Conclusion We revealed inflammatory characteristics that serve as a peripheral blood transcriptomic signature for sciatica and identified genes that are essential for mRNA dysregulation in the peripheral blood of patients with sciatica.

scholarly journals Condensing Life Substances within the House: The Rice-Boiling Shuhi of Southwest China

2017 ◽  
Vol 71 (1) ◽  
Author(s):  
Elisabeth Hsu ◽  
Franz K. Huber ◽  
Caroline S. Weckerle
Keyword(s):  
Tibetan Plateau ◽  
Southeast Asia ◽  
High Altitude ◽  
Sea Level ◽  
Ethnic Groups ◽  
Southwest China ◽  
Cultural Practice ◽  
The Tibetan Plateau ◽  
Regional Culture ◽  
Fault Line

AbstractThe Shuhi of Muli County, Sichuan Province, are one of multiple ethnic groups inhabiting the river gorges of the Qinghai-Gansu-Sichuan corridor between the Tibetan plateau and the Chinese lowlands. The Shuhi have grown paddy rice since times immemorial at an unusually high altitude (ca. 2,300 m above sea level). This article aims to explain this conundrum not merely through the ecology (as is common among Tibetan area specialists), but by researching the cultivation and consumption of rice as a historically-evolved cultural practice. According to a recently formulated agro-archaeological hypothesis regarding the macro-region of Eurasia, it is possible to identify two supra-regional culture complexes distinguished by their respective culinary technologies: rice-boiling versus wheat-grinding-and-baking. The hypothesis posits that the fault line between the two supra-regional cultural complexes is precisely along this river gorges corridor. In this article we provide support for this hypothesis arguing that Shuhi ritual and kinship practices have much affinity with those of other rice-boiling peoples in Southeast Asia, whereas certain of their current religious practices are shared with the wheat-grinding Tibetans.

scholarly journals Expression and hypoxia adaptation analysis of the EPO gene in different tissues of plateau Tibetan pigs

2015 ◽  
Vol 14 (1) ◽  
pp. 1700-1706 ◽  
Author(s):  
B.Z. Deji ◽  
P. Shang ◽  
W.J. Danzeng ◽  
H. Zhang ◽  
Y.Z. Qiangba
Keyword(s):  
Tibetan Pigs ◽  
Hypoxia Adaptation ◽  
Different Tissues

scholarly journals A comparative analysis of differentially expressed mRNAs, miRNAs and circRNAs provides insights into the key genes involved in the high-altitude adaptation of yaks

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Qianyun Ge ◽  
Yongbo Guo ◽  
Wangshan Zheng ◽  
Yuan Cai ◽  
Xuebin Qi ◽  
...  
Keyword(s):  
High Altitude ◽  
Molecular Mechanisms ◽  
Regulation Of Gene Expression ◽  
Differentially Expressed ◽  
The Tibetan Plateau ◽  
The Core ◽  
Processing Pathways ◽  
Genetic Information Processing ◽  
Altitude Adaptation ◽  
The Difference

Abstract Background Yaks that inhabit the Tibetan Plateau exhibit striking phenotypic and physiological differences from cattle and have adapted well to the extreme conditions on the plateau. However, the mechanisms used by these animals for the regulation of gene expression at high altitude are not fully understood. Results Here, we sequenced nine lung transcriptomes of yaks at altitudes of 3400, 4200 and 5000 m, and low-altitude Zaosheng cattle, which is a closely related species, served as controls. The analysis identified 21,764 mRNAs, 1377 circRNAs and 1209 miRNAs. By comparing yaks and cattle, 4975 mRNAs, 252 circRNAs and 75 miRNAs were identified differentially expressed. By comparing yaks at different altitudes, we identified 756 mRNAs, 64 circRNAs and 83 miRNAs that were differentially expressed (fold change ≥2 and P-value < 0.05). The pathways enriched in the mRNAs, circRNAs and miRNAs identified from the comparison of yaks and cattle were mainly associated with metabolism, including ‘glycosaminoglycan degradation’, ‘pentose and glucuronate interconversions’ and ‘flavone and flavonol biosynthesis’, and the mRNAs, circRNAs and miRNAs identified from the comparison of yaks at different altitude gradients were significantly enriched in metabolic pathways and immune and genetic information processing pathways. The core RNAs were identified from the mRNA-miRNA-circRNA networks constructed using the predominant differentially expressed RNAs. The core genes specific to the difference between yaks and cattle were associated with the endoplasmic reticulum and fat deposition, but those identified from the comparison among yaks at different altitude gradients were associated with maintenance of the normal biological functions of cells. Conclusions This study enhances our understanding of the molecular mechanisms involved in hypoxic adaptation in yaks and might contribute to improvements in the understanding and prevention of hypoxia-related diseases.

scholarly journals The Expression Regulatory Network in the Lung Tissue of Tibetan Pigs Provides Insight Into Hypoxia-Sensitive Pathways in High-Altitude Hypoxia

2021 ◽  
Vol 12 ◽  
Author(s):  
Yanan Yang ◽  
Haonan Yuan ◽  
Tianliang Yang ◽  
Yongqing Li ◽  
Caixia Gao ◽  
...  
Keyword(s):  
High Altitude ◽  
Regulatory Networks ◽  
Alveolar Wall ◽  
Potential Candidate ◽  
Low Oxygen ◽  
Structure Damage ◽  
High Altitude Adaptation ◽  
Tibetan Pigs ◽  
Altitude Adaptation ◽  
Insight Into

To adapt to a low-oxygen environment, Tibetan pigs have developed a series of unique characteristics and can transport oxygen more effectively; however, the regulation of the associated processes in high-altitude animals remains elusive. We performed mRNA-seq and miRNA-seq, and we constructed coexpression regulatory networks of the lung tissues of Tibetan and Landrace pigs. HBB, AGT, COL1A2, and EPHX1 were identified as major regulators of hypoxia-induced genes that regulate blood pressure and circulation, and they were enriched in pathways related to signal transduction and angiogenesis, such as HIF-1, PI3K-Akt, mTOR, and AMPK. HBB may promote the combination of hemoglobin and oxygen as well as angiogenesis for high-altitude adaptation in Tibetan pigs. The expression of MMP2 showed a similar tendency of alveolar septum thickness among the four groups. These results indicated that MMP2 activity may lead to widening of the alveolar wall and septum, alveolar structure damage, and collapse of alveolar space with remarkable fibrosis. These findings provide a perspective on hypoxia-adaptive genes in the lungs in addition to insights into potential candidate genes in Tibetan pigs for further research in the field of high-altitude adaptation.

scholarly journals Genetic variation in haemoglobin alters breathing in high-altitude deer mice

2021 ◽  
Author(s):  
Catherine M. Ivy ◽  
Oliver H. Wearing ◽  
Chandrasekhar Natarajan ◽  
Rena M. Schweizer ◽  
Natalia Gutiérrez-Pinto ◽  
...  
Keyword(s):  
Genetic Variation ◽  
High Altitude ◽  
Globin Gene ◽  
Respiratory Physiology ◽  
Deer Mice ◽  
Emergent Properties ◽  
Mixed Genetic Background ◽  
Hypoxia Adaptation ◽  
Globin Gene Expression

ABSTRACTPhysiological systems often have emergent properties but the effects of genetic variation on physiology are often unknown, which presents a major challenge to understanding the mechanisms of phenotypic evolution. We investigated the in vivo effects on respiratory physiology of genetic variants in haemoglobin (Hb) that contribute to hypoxia adaptation in high-altitude deer mice (Peromyscus maniculatus). We created F2 inter-population hybrids of highland and lowland deer mice to test the phenotypic effects of α- and β-globin variants on a mixed genetic background. High-altitude genotypes were associated with breathing phenotypes that enhance O2 uptake in hypoxia, including a deeper more effective breathing pattern and an augmented hypoxic ventilatory response. These effects could not be explained by erythrocyte Hb-O2 affinity or globin gene expression in the brainstem. Therefore, adaptive variation in haemoglobin can have unexpected effects on physiology that are distinct from the canonical function of this protein in circulatory O2 transport.

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