title: Repression of hypoxia-inducible factor α signaling by Set7-mediated methylation.
abstract: Hypoxia-inducible factor (HIF)-1α and HIF-2α are the main regulators of cellular responses to hypoxia. Post-translational modifications of HIF-1α and 2α are necessary to modulate their functions. The methylation of non-histone proteins by Set7, an SET domain-containing lysine methyltransferase, is a novel regulatory mechanism to control cell protein function in response to various cellular stresses. In this study, we show that Set7 methylates HIF-1α at lysine 32 and HIF-2α at lysine K29; this methylation inhibits the expression of HIF-1α/2α targets by impairing the occupancy of HIF-α on hypoxia response element of HIF target gene promoter. Set7-null fibroblasts and the cells with shRNA-knocked down Set7 exhibit upregulated HIF target genes. Set7 inhibitor blocks HIF-1α/2α methylation to enhance HIF target gene expression. Set7-null fibroblasts and the cells with shRNA-knocked down Set7 or inhibition of Set7 by the inhibitor subjected to hypoxia display an increased glucose uptake and intracellular adenosine triphosphate levels. These findings define a novel modification of HIF-1α/2α and demonstrate that Set7-medited lysine methylation negatively regulates HIF-α transcriptional activity and HIF-1α-mediated glucose homeostasis.
authors.affiliation: State Key Laboratory of Freshwater Ecology and Biotechnology Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, P. R. China The Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, P. R. China.
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.affiliation: The Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, P. R. China Department of Reproduction, Maternal and Child Health Hospital of Hubei Province, Wuhan, 430070, P. R. China.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Freshwater Ecology and Biotechnology Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, P. R. China The Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, P. R. China.
authors.forename: Chenxi
authors.initials: C
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Freshwater Ecology and Biotechnology Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, P. R. China The Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, P. R. China.
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Leng
authors.affiliation: State Key Laboratory of Freshwater Ecology and Biotechnology Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, P. R. China The Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, P. R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Cao
authors.affiliation: The Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, P. R. China.
authors.forename: Gang
authors.initials: G
authors.lastname: Ouyang
authors.affiliation: State Key Laboratory of Freshwater Ecology and Biotechnology Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, P. R. China The Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, P. R. China w-xiao@ihb.ac.cn.
authors.forename: Wuhan
authors.initials: W
authors.lastname: Xiao
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015687:Cell Hypoxia; D002460:Cell Line; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D051379:Mice; D015398:Signal Transduction; D014158:Transcription, Genetic; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005947:Glucose; D011495:Histone-Lysine N-Methyltransferase; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008239:Lysine; D000099162:Endothelial PAS Domain-Containing Protein 1; C540312:SETD7 protein, human