Transcriptome and network changes in climbers at extreme altitudes

Fang Chen; Wei Zhang; Yu Liang; Jialiang Huang; Kui Li; Christopher D. Green; Jiancheng Liu; Guojie Zhang; Bing Zhou; Xin Yi; Wei Wang; Hang Liu; Xiaohong Xu; Feng Shen; Ning Qu; Yading Wang; Guoyi Gao; A. San; LuoSang JiangBai; Hua Sang; Xiangdong Fang; Karsten Kristiansen; Huanming Yang; Jun Wang; Jing-Dong J. Han; Jian Wang

doi:10.1371/journal.pone.0031645

Transcriptome and network changes in climbers at extreme altitudes

Fang Chen, Wei Zhang, Yu Liang, Jialiang Huang, Kui Li, Christopher D. Green, Jiancheng Liu, Guojie Zhang, Bing Zhou, Xin Yi, Wei Wang, Hang Liu, Xiaohong Xu, Feng Shen, Ning Qu, Yading Wang, Guoyi Gao, A. San, LuoSang JiangBai, Hua SangXiangdong Fang, Karsten Kristiansen, Huanming Yang, Jun Wang, Jing-Dong J. Han, Jian Wang

Department of Biology

20 Citations (Scopus)

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Abstract

Extreme altitude can induce a range of cellular and systemic responses. Although it is known that hypoxia underlies the major changes and that the physiological responses include hemodynamic changes and erythropoiesis, the molecular mechanisms and signaling pathways mediating such changes are largely unknown. To obtain a more complete picture of the transcriptional regulatory landscape and networks involved in extreme altitude response, we followed four climbers on an expedition up Mount Xixiabangma (8,012 m), and collected blood samples at four stages during the climb for mRNA and miRNA expression assays. By analyzing dynamic changes of gene networks in response to extreme altitudes, we uncovered a highly modular network with 7 modules of various functions that changed in response to extreme altitudes. The erythrocyte differentiation module is the most prominently up-regulated, reflecting increased erythrocyte differentiation from hematopoietic stem cells, probably at the expense of differentiation into other cell lineages. These changes are accompanied by coordinated down-regulation of general translation. Network topology and flow analyses also uncovered regulators known to modulate hypoxia responses and erythrocyte development, as well as unknown regulators, such as the OCT4 gene, an important regulator in stem cells and assumed to only function in stem cells. We predicted computationally and validated experimentally that increased OCT4 expression at extreme altitude can directly elevate the expression of hemoglobin genes. Our approach established a new framework for analyzing the transcriptional regulatory network from a very limited number of samples.

Original language	English
Journal	P L o S One
Volume	7
Issue number	2
Pages (from-to)	e31645-e31645
ISSN	1932-6203
DOIs	https://doi.org/10.1371/journal.pone.0031645
Publication status	Published - 29 Feb 2012

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Chen, F, Zhang, W, Liang, Y, Huang, J, Li, K, Green, CD, Liu, J, Zhang, G, Zhou, B, Yi, X, Wang, W, Liu, H, Xu, X, Shen, F, Qu, N, Wang, Y, Gao, G, San, A, JiangBai, L, Sang, H, Fang, X, Kristiansen, K, Yang, H, Wang, J, Han, J-DJ & Wang, J 2012, 'Transcriptome and network changes in climbers at extreme altitudes', P L o S One, vol. 7, no. 2, pp. e31645-e31645. https://doi.org/10.1371/journal.pone.0031645

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abstract = "Extreme altitude can induce a range of cellular and systemic responses. Although it is known that hypoxia underlies the major changes and that the physiological responses include hemodynamic changes and erythropoiesis, the molecular mechanisms and signaling pathways mediating such changes are largely unknown. To obtain a more complete picture of the transcriptional regulatory landscape and networks involved in extreme altitude response, we followed four climbers on an expedition up Mount Xixiabangma (8,012 m), and collected blood samples at four stages during the climb for mRNA and miRNA expression assays. By analyzing dynamic changes of gene networks in response to extreme altitudes, we uncovered a highly modular network with 7 modules of various functions that changed in response to extreme altitudes. The erythrocyte differentiation module is the most prominently up-regulated, reflecting increased erythrocyte differentiation from hematopoietic stem cells, probably at the expense of differentiation into other cell lineages. These changes are accompanied by coordinated down-regulation of general translation. Network topology and flow analyses also uncovered regulators known to modulate hypoxia responses and erythrocyte development, as well as unknown regulators, such as the OCT4 gene, an important regulator in stem cells and assumed to only function in stem cells. We predicted computationally and validated experimentally that increased OCT4 expression at extreme altitude can directly elevate the expression of hemoglobin genes. Our approach established a new framework for analyzing the transcriptional regulatory network from a very limited number of samples.",

author = "Fang Chen and Wei Zhang and Yu Liang and Jialiang Huang and Kui Li and Green, {Christopher D.} and Jiancheng Liu and Guojie Zhang and Bing Zhou and Xin Yi and Wei Wang and Hang Liu and Xiaohong Xu and Feng Shen and Ning Qu and Yading Wang and Guoyi Gao and A. San and LuoSang JiangBai and Hua Sang and Xiangdong Fang and Karsten Kristiansen and Huanming Yang and Jun Wang and Han, {Jing-Dong J.} and Jian Wang",

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AU - Green, Christopher D.

AU - Liu, Jiancheng

AU - Zhang, Guojie

AU - Zhou, Bing

AU - Yi, Xin

AU - Wang, Wei

AU - Liu, Hang

AU - Xu, Xiaohong

AU - Shen, Feng

AU - Qu, Ning

AU - Wang, Yading

AU - Gao, Guoyi

AU - San, A.

AU - JiangBai, LuoSang

AU - Sang, Hua

AU - Fang, Xiangdong

AU - Kristiansen, Karsten

AU - Yang, Huanming

AU - Wang, Jun

AU - Han, Jing-Dong J.

AU - Wang, Jian

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N2 - Extreme altitude can induce a range of cellular and systemic responses. Although it is known that hypoxia underlies the major changes and that the physiological responses include hemodynamic changes and erythropoiesis, the molecular mechanisms and signaling pathways mediating such changes are largely unknown. To obtain a more complete picture of the transcriptional regulatory landscape and networks involved in extreme altitude response, we followed four climbers on an expedition up Mount Xixiabangma (8,012 m), and collected blood samples at four stages during the climb for mRNA and miRNA expression assays. By analyzing dynamic changes of gene networks in response to extreme altitudes, we uncovered a highly modular network with 7 modules of various functions that changed in response to extreme altitudes. The erythrocyte differentiation module is the most prominently up-regulated, reflecting increased erythrocyte differentiation from hematopoietic stem cells, probably at the expense of differentiation into other cell lineages. These changes are accompanied by coordinated down-regulation of general translation. Network topology and flow analyses also uncovered regulators known to modulate hypoxia responses and erythrocyte development, as well as unknown regulators, such as the OCT4 gene, an important regulator in stem cells and assumed to only function in stem cells. We predicted computationally and validated experimentally that increased OCT4 expression at extreme altitude can directly elevate the expression of hemoglobin genes. Our approach established a new framework for analyzing the transcriptional regulatory network from a very limited number of samples.

AB - Extreme altitude can induce a range of cellular and systemic responses. Although it is known that hypoxia underlies the major changes and that the physiological responses include hemodynamic changes and erythropoiesis, the molecular mechanisms and signaling pathways mediating such changes are largely unknown. To obtain a more complete picture of the transcriptional regulatory landscape and networks involved in extreme altitude response, we followed four climbers on an expedition up Mount Xixiabangma (8,012 m), and collected blood samples at four stages during the climb for mRNA and miRNA expression assays. By analyzing dynamic changes of gene networks in response to extreme altitudes, we uncovered a highly modular network with 7 modules of various functions that changed in response to extreme altitudes. The erythrocyte differentiation module is the most prominently up-regulated, reflecting increased erythrocyte differentiation from hematopoietic stem cells, probably at the expense of differentiation into other cell lineages. These changes are accompanied by coordinated down-regulation of general translation. Network topology and flow analyses also uncovered regulators known to modulate hypoxia responses and erythrocyte development, as well as unknown regulators, such as the OCT4 gene, an important regulator in stem cells and assumed to only function in stem cells. We predicted computationally and validated experimentally that increased OCT4 expression at extreme altitude can directly elevate the expression of hemoglobin genes. Our approach established a new framework for analyzing the transcriptional regulatory network from a very limited number of samples.

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