title: Acute hypoxia affects P-TEFb through HDAC3 and HEXIM1-dependent mechanism to promote gene-specific transcriptional repression.
abstract: Hypoxia is associated with a variety of physiological and pathological conditions and elicits specific transcriptional responses. The elongation competence of RNA Polymerase II is regulated by the positive transcription elongation factor b (P-TEFb)-dependent phosphorylation of Ser2 residues on its C-terminal domain. Here, we report that hypoxia inhibits transcription at the level of elongation. The mechanism involves enhanced formation of inactive complex of P-TEFb with its inhibitor HEXIM1 in an HDAC3-dependent manner. Microarray transcriptome profiling of hypoxia primary response genes identified ∼79% of these genes being HEXIM1-dependent. Hypoxic repression of P-TEFb was associated with reduced acetylation of its Cdk9 and Cyclin T1 subunits. Hypoxia caused nuclear translocation and co-localization of the Cdk9 and HDAC3/N-CoR repressor complex. We demonstrated that the described mechanism is involved in hypoxic repression of the monocyte chemoattractant protein-1 (MCP-1) gene. Thus, HEXIM1 and HDAC-dependent deacetylation of Cdk9 and Cyclin T1 in response to hypoxia signalling alters the P-TEFb functional equilibrium, resulting in repression of transcription.
authors: Department of Cellular Physiological Chemistry, Graduate School, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8549, Japan Global Center of Excellence Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8549, Japan.
authors: Olga S
authors: OS
authors: Safronova
authors: Department of Cellular Physiological Chemistry, Graduate School, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8549, Japan.
authors: Ken-Ichi
authors: K
authors: Nakahama
authors: Department of Cellular Physiological Chemistry, Graduate School, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8549, Japan Global Center of Excellence Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8549, Japan morita.cell@tmd.ac.jp.
authors: Ikuo
authors: I
authors: Morita
mesh_terms: D000107:Acetylation; D021581:Active Transport, Cell Nucleus; D015687:Cell Hypoxia; D002467:Cell Nucleus / Q000201:enzymology; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D056906:Cyclin T / Q000378:metabolism; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D056971:Nuclear Receptor Co-Repressor 1 / Q000378:metabolism; D010766:Phosphorylation; D042925:Positive Transcriptional Elongation Factor B / Q000737:chemistry / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D016601:RNA-Binding Proteins / Q000502:physiology*; D012694:Serine / Q000378:metabolism; D061805:Transcription Elongation, Genetic; D014157:Transcription Factors; D059467:Transcriptome; D000099186:Histone Deacetylase 3
chemical_list: D018932:Chemokine CCL2; D056906:Cyclin T; D042863:Cyclin-Dependent Kinase 9; D006655:Histone Deacetylases; D056971:Nuclear Receptor Co-Repressor 1; D042925:Positive Transcriptional Elongation Factor B; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012694:Serine; D014157:Transcription Factors; D000099186:Histone Deacetylase 3; C476123:HEXIM1 protein, human