Acute hypoxia affects P-TEFb through HDAC3 and HEXIM1-dependent mechanism to promote gene-specific transcriptional repression.
Acute hypoxia affects P-TEFb through HDAC3 and HEXIM1-dependent mechanism to promote gene-specific transcriptional repression.
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DOI：
10.1093/nar/gku611
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发表时间：
2014-08
影响因子：
14.9
通讯作者：
Morita I
中科院分区：
文献类型：
--
作者：
Safronova OS;Nakahama K;Morita I
缺氧与多种生理和病理状况相关，并引发特定的转录反应。RNA聚合酶II的延伸能力受正转录延伸因子B（P-TEF B）依赖的其C-末端结构域上Ser 2残基的磷酸化调节。在这里，我们报告说，缺氧抑制转录水平的延伸。该机制涉及以HDAC 3依赖性方式增强P-TEFb与其抑制剂HEXIM 1的非活性复合物的形成。缺氧初级反应基因的微阵列转录组分析确定了这些基因中的约79%是HEXIM 1依赖性的。P-TEFb的低表达抑制与其Cdk 9和Cyclin T1亚基的乙酰化减少有关。缺氧引起Cdk 9和HDAC 3/N-CoR阻遏物复合物的核转位和共定位。我们证明，所描述的机制是参与低氧抑制的单核细胞趋化蛋白-1（MCP-1）基因。因此，HEXIM 1和HDAC依赖性的Cdk 9和细胞周期蛋白T1的去乙酰化反应，以响应缺氧信号改变P-TEFb功能平衡，导致转录抑制。
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.
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DOI：
10.4161/cc.9.9.11346
发表时间：
2010-05
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Cho S;Schroeder S;Ott M
通讯作者：
Ott M
影响因子：
5.3
作者：
Guenther, MG;Barak, O;Lazar, MA
通讯作者：
Lazar, MA
影响因子：
4.4
作者：
Kirwan, Ruaidhri P.;Felice, Luca;Leonard, Martin O.
通讯作者：
Leonard, Martin O.
影响因子：
11.4
作者：
Cho, Sungyoo;Schroeder, Sebastian;Ott, Melanie
通讯作者：
Ott, Melanie
影响因子：
64.5
作者：
Guenther, Matthew G.;Levine, Stuart S.;Young, Richard A.
通讯作者：
Young, Richard A.