Acute hypoxia affects P-TEFb through HDAC3 and HEXIM1-dependent mechanism to promote gene-specific transcriptional repression

摘要

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 similar to 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.