Histone ADP-Ribosylation Facilitates Gene Transcription by Directly Remodeling Nucleosomes
Histone ADP-Ribosylation Facilitates Gene Transcription by Directly Remodeling Nucleosomes
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DOI：
10.1128/mcb.06667-11
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发表时间：
2012-07-01
影响因子：
5.3
通讯作者：
Ha, Hyo Chol
中科院分区：
文献类型：
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作者：
Martinez-Zamudio, Ricardo;Ha, Hyo Chol
DNA包装入核小体对基因转录造成障碍，组蛋白修饰和核小体重塑复合物协同工作以减轻这些障碍从而促进转录。新出现的证据表明，染色质相关的聚（ADP-核糖）聚合酶1（PARP-1）及其酶活性促进炎症基因转录和调节动物模型中的炎症反应。然而，PARP-1酶促活性促进转录的分子机制还不清楚。在这里，我们表明，通过细胞内信号通路，脂多糖（LPS）刺激诱导PARP-1酶活性和ADP-核糖基化的组蛋白在转录活性和可访问的染色质区域的巨噬细胞。体外DNA酶I足迹法和限制性内切酶可及性分析表明，组蛋白ADP-核糖基化直接破坏核小体中组蛋白-DNA相互作用的稳定性，并增加核小体DNA对核酸酶的位点可及性。与此一致，LPS刺激诱导的在il-1 β、mip-2和csf 2的核小体占据的启动子处的ADP核糖基化促进NF-κ B募集和这些基因在巨噬细胞中的转录。因此，我们的数据表明，PARP-1酶活性通过组蛋白ADP-核糖基化增加启动子可及性来促进基因转录。
The packaging of DNA into nucleosomes imposes obstacles on gene transcription, and histone-modifying and nucleosome-remodeling complexes work in concert to alleviate these obstacles so as to facilitate transcription. Emerging evidence shows that chromatin-associated poly(ADP-ribose) polymerase 1 (PARP-1) and its enzymatic activity facilitate inflammatory gene transcription and modulate the inflammatory response in animal models. However, the molecular mechanisms by which PARP-1 enzymatic activity facilitates transcription are not well understood. Here we show that through an intracellular signaling pathway, lipopolysaccharide (LPS) stimulation induces PARP-1 enzymatic activity and the ADP-ribosylation of histones at transcriptionally active and accessible chromatin regions in macrophages. In vitro DNase I footprinting and restriction endonuclease accessibility assays reveal that histone ADP-ribosylation directly destabilizes histone-DNA interactions in the nucleosome and increases the site accessibility of the nucleosomal DNA to nucleases. Consistent with this, LPS stimulation-induced ADP-ribosylation at the nucleosome-occupied promoters of il-1 beta, mip-2, and csf2 facilitates NF-kappa B recruitment and the transcription of these genes in macrophages. Therefore, our data suggest that PARP-1 enzymatic activity facilitates gene transcription through increasing promoter accessibility by histone ADP-ribosylation.