Helicobacter pylori-induced histone modification, associated gene expression in gastric epithelial cells, and its implication in pathogenesis.
Helicobacter pylori-induced histone modification, associated gene expression in gastric epithelial cells, and its implication in pathogenesis.
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DOI：
10.1371/journal.pone.0009875
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发表时间：
2010-04-01
期刊：
影响因子：
3.7
通讯作者：
Goldberg JB
中科院分区：
文献类型：
--
作者：
Ding SZ;Fischer W;Kaparakis-Liaskos M;Liechti G;Merrell DS;Grant PA;Ferrero RL;Crowe SE;Haas R;Hatakeyama M;Goldberg JB
组蛋白修饰对于调节基因表达、细胞周期、细胞增殖和发育至关重要。相对较少的研究调查人类胃病的主要原因幽门螺杆菌是否影响组蛋白修饰。因此，我们研究了幽门螺杆菌感染对胃上皮细胞中组蛋白修饰的整体和启动子特异性的影响。野生型幽门螺杆菌感染胃上皮细胞会诱导组蛋白 H3 丝氨酸 10 (H3 Ser10) 发生时间和剂量依赖性去磷酸化，并降低 H3 赖氨酸 23 的乙酰化，但对其他七个特定修饰没有影响。不同的含有 cag 致病性岛 (PAI) 的临床分离株表现出相似的诱导 H3 Ser10 去磷酸化的能力。 cagA、vacA、不可磷酸化的 CagA 突变体 cagAEPISA 的突变或鞭毛的破坏没有显示任何影响，而删除整个 cagPAI 将 H3 Ser10 磷酸化恢复到对照水平。对 27 个 cagPAI 突变体的分析表明，引起 H3 Ser10 去磷酸化的基因与之前发现的诱导白细胞介素 8 的基因相似，与 CagA 易位无关。这种效应独立于 ERK 或 p38 途径和 I 型干扰素信号传导。此外，c-Jun 和 hsp70 基因表达与该组蛋白修饰相关。这些结果表明，幽门螺杆菌通过不依赖 cagA、vacA、但依赖 cagPAI 的机制改变组蛋白修饰和宿主反应，这有助于其持续感染和发病机制。
Histone modifications are critical in regulating gene expression, cell cycle, cell proliferation, and development. Relatively few studies have investigated whether Helicobacter pylori, the major cause of human gastric diseases, affects histone modification. We therefore investigated the effects of H. pylori infection on histone modifications in a global and promoter-specific manner in gastric epithelial cells. Infection of gastric epithelial cells by wild-type H. pylori induced time- and dose-dependent dephosphorylation of histone H3 at serine 10 (H3 Ser10) and decreased acetylation of H3 lysine 23, but had no effects on seven other specific modifications. Different cag pathogenicity island (PAI)-containing-clinical isolates showed similar abilities to induce H3 Ser10 dephosphorylation. Mutation of cagA, vacA, nonphosphorylateable CagA mutant cagAEPISA, or disruption of the flagella showed no effects, while deletion of the entire cagPAI restored the H3 Ser10 phosphorylation to control levels. Analysis of 27 cagPAI mutants indicated that the genes that caused H3 Ser10 dephosphorylation were similar to those that were previously found to induce interleukin-8, irrespective of CagA translocation. This effect was independent of ERK or p38 pathways and type I interferon signaling. Additionally, c-Jun and hsp70 gene expression was associated with this histone modification. These results demonstrate that H. pylori alters histone modification and host response via a cagA-, vacA-independent, but cagPAI-dependent mechanisms, which contribute to its persistent infection and pathogenesis.
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