title: Two functional loci in the promoter of EPAS1 gene involved in high-altitude adaptation of Tibetans.
abstract: EPAS1 involves in the hypoxic response and is suggested to be responsible for the genetic adaptation of high-altitude hypoxia in Tibetans. However, the detailed molecular mechanism remains unknown. In this study, a single nucleotide polymorphism rs56721780:G>C and an insertion/deletion (indel) polymorphism -742 indel in the promoter region showed divergence between Tibetans and non-Tibetan lowlanders. rs56721780:G>C regulated the transcription of EPAS1 by IKAROS family zinc finger 1 (IKZF1), which was identified as a new transcriptional repressor for EPAS1 gene. It demonstrated that the C allele of rs56721780:G>C decreased the binding of IKZF1, leading to the attenuated transcriptional repression of EPAS1 gene. The insertion at -742 indel provided a new binding site for Sp1 and was related to the activation of EPAS1 promoter. Further functional analysis revealed that lysyl oxidase (LOX) gene, which was reported to be responsible for extracellular matrix protein cross-linking of amnion previously, was a direct target of EPAS1. The CC genotype at rs56721780:G>C and the insertion genotype at -742 indel were found associated with higher EPAS1 and LOX expression levels in amnion, as well as higher birth weight of Tibetan newborns, suggesting that EPAS1 gene might play important roles in the development of amnion, fetus growth and high-altitude adaptation of Tibetans.
authors.affiliation: State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University Jiangwan Campus, 2005 Songhu Road, Shanghai 200438, P.R. China.
authors.forename: Xiang-Hong
authors.initials: XH
authors.lastname: Xu
authors.affiliation: 1] Clinical laboratory of Huadong Sanatorium, Dajishan, Meiyuan Garden, Wuxi, Jiangsu 214065, P.R. China [2] Public Health Bureau for Shigatse District, 5 Keji Road, Shigatse District, Tibet 857000, P.R. China.
authors.forename: Xue-Wen
authors.initials: XW
authors.lastname: Huang
authors.affiliation: Department of Gynecology and Obstetrics, The People's Hospital of Shigatse District, 28 Shanghai Middle Road, Shigatse District, Tibet 857000, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Qun
authors.affiliation: State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University Jiangwan Campus, 2005 Songhu Road, Shanghai 200438, P.R. China.
authors.forename: Ya-Nan
authors.initials: YN
authors.lastname: Li
authors.affiliation: State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University Jiangwan Campus, 2005 Songhu Road, Shanghai 200438, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Life Sciences, Fudan University Jiangwan Campus, 2005 Songhu Road, Shanghai 200438, P.R. China.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University Jiangwan Campus, 2005 Songhu Road, Shanghai 200438, P.R. China.
authors.forename: Yanyun
authors.initials: Y
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University Jiangwan Campus, 2005 Songhu Road, Shanghai 200438, P.R. China.
authors.forename: Qing-Mei
authors.initials: QM
authors.lastname: Liu
authors.affiliation: 1] School of Life Sciences, Fudan University Jiangwan Campus, 2005 Songhu Road, Shanghai 200438, P.R. China [2] Center for Reproductive Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200135, P.R. China.
authors.forename: Kang
authors.initials: K
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University Jiangwan Campus, 2005 Songhu Road, Shanghai 200438, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
authors.affiliation: State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University Jiangwan Campus, 2005 Songhu Road, Shanghai 200438, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center for Genetics and Development, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University Jiangwan Campus, 2005 Songhu Road, Shanghai 200438, P.R. China.
authors.forename: Jiucun
authors.initials: J
authors.lastname: Wang
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics*; D000531:Altitude; D000650:Amnion / Q000166:cytology / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D001724:Birth Weight / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D005260:Female; D005312:Fetal Blood / Q000166:cytology / Q000378:metabolism; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics; D007231:Infant, Newborn; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012641:Selection, Genetic / Q000235:genetics; D018609:Tibet; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051740:Ikaros Transcription Factor; D008249:Protein-Lysine 6-Oxidase; D012333:RNA, Messenger; D000099162:Endothelial PAS Domain-Containing Protein 1; C497239:IKZF1 protein, human