The transcriptional repressor Hes1 attenuates inflammation by regulating transcription elongation.
The transcriptional repressor Hes1 attenuates inflammation by regulating transcription elongation.
复制标题
DOI：
10.1038/ni.3486
复制
发表时间：
2016-08
影响因子：
30.5
通讯作者：
Hu X
中科院分区：
文献类型：
--
作者：
Shang Y;Coppo M;He T;Ning F;Yu L;Kang L;Zhang B;Ju C;Qiao Y;Zhao B;Gessler M;Rogatsky I;Hu X
大多数已知的抑制炎症基因表达的调控机制针对转录前启动步骤，而启动后调控炎症基因表达的证据仍然很少。在这里，我们展示了转录抑制因子Hes1(Hes1)抑制CXCL1的产生，CXCL1是一种对招募中性粒细胞至关重要的趋化因子。HES1以一种依赖于巨噬细胞产生的CXCL1的方式负向调节体内中性粒细胞的募集，并减轻炎性关节炎的严重程度。从机制上讲，Hes1对CXCL1表达的抑制并不涉及转录启动的修饰。相反，Hes1抑制信号诱导的正转录延伸复合体P-TEFb的招募，从而阻止RNA聚合酶II在丝氨酸-2上的磷酸化和生产性延伸。因此，我们的结果确定Hes1是一种炎症反应的动态平衡抑制因子，它通过调节转录伸长来发挥其抑制功能。
Most of the known regulatory mechanisms that curb inflammatory gene expression target pre-transcription initiation steps and evidence for regulation of inflammatory gene expression post initiation remains scarce. Here we show that transcription repressor hairy and enhancer of split 1 (Hes1) suppresses production of CXCL1, a chemokine crucial for recruiting neutrophils. Hes1 negatively regulates neutrophil recruitment in vivo in a manner that is dependent on macrophage-produced CXCL1 and attenuates severity of inflammatory arthritis. Mechanistically, inhibition of Cxcl1 expression by Hes1 does not involve modification of transcription initiation. Instead, Hes1 inhibits signal-induced recruitment of positive transcription elongation complex P-TEFb, thereby preventing phosphorylation of RNA polymerase II on serine-2 and productive elongation. Thus, our results identify Hes1 as a homeostatic suppressor of inflammatory responses which exerts its suppressive function by regulating transcription elongation.