title: Transcriptome and network changes in climbers at extreme altitudes.
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.
authors.affiliation: BGI Shenzhen, Shenzhen, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Yu
authors.initials: Y
authors.lastname: Liang
authors.forename: Jialiang
authors.initials: J
authors.lastname: Huang
authors.forename: Kui
authors.initials: K
authors.lastname: Li
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Green
authors.forename: Jiancheng
authors.initials: J
authors.lastname: Liu
authors.forename: Guojie
authors.initials: G
authors.lastname: Zhang
authors.forename: Bing
authors.initials: B
authors.lastname: Zhou
authors.forename: Xin
authors.initials: X
authors.lastname: Yi
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Hang
authors.initials: H
authors.lastname: Liu
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Xu
authors.forename: Feng
authors.initials: F
authors.lastname: Shen
authors.forename: Ning
authors.initials: N
authors.lastname: Qu
authors.forename: Yading
authors.initials: Y
authors.lastname: Wang
authors.forename: Guoyi
authors.initials: G
authors.lastname: Gao
authors.forename: A
authors.initials: A
authors.lastname: San
authors.forename: LuoSang
authors.initials: L
authors.lastname: JiangBai
authors.forename: Hua
authors.initials: H
authors.lastname: Sang
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Fang
authors.forename: Karsten
authors.initials: K
authors.lastname: Kristiansen
authors.forename: Huanming
authors.initials: H
authors.lastname: Yang
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Jing-Dong J
authors.initials: JD
authors.lastname: Han
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
mesh_terms: D000328:Adult; D000531:Altitude; D001665:Binding Sites; D002454:Cell Differentiation; D019070:Cell Lineage; D004912:Erythrocytes / Q000166:cytology; D005260:Female; D020869:Gene Expression Profiling; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D000860:Hypoxia; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D008875:Middle Aged; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis* / Q000737:chemistry; D010100:Oxygen / Q000378:metabolism; D025341:Principal Component Analysis; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic; D059467:Transcriptome; D015854:Up-Regulation
chemical_list: D035683:MicroRNAs; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D012333:RNA, Messenger; D010100:Oxygen