BACKGROUND Nickel is an occupational and environmental toxicant associated with a number of diseases in humans including pulmonary fibrosis, bronchitis and lung and nasal cancers. Our earlier studies showed that the nickel-exposure-induced genome-wide transcriptional changes, which persist even after the termination of exposure may underlie nickel pathogenesis. However, the mechanisms that drive nickel-induced persistent changes to the transcriptome remain elusive. RESULTS To elucidate the mechanisms that underlie nickel-induced long-term transcriptional changes, in this study, we examined the transcriptome and the epigenome of human lung epithelial cells during nickel exposure and after the termination of exposure. We identified two categories of persistently differentially expressed genes: (i) the genes that were differentially expressed during nickel exposure; and (ii) the genes that were differentially expressed only after the termination of exposure. Interestingly, > 85% of the nickel-induced gene expression changes occurred only after the termination of exposure. We also found extensive genome-wide alterations to the activating histone modification, H3K4me3, after the termination of nickel exposure, which coincided with the post-exposure gene expression changes. In addition, we found significant post-exposure alterations to the repressive histone modification, H3K27me3. CONCLUSION Our results suggest that while modest first wave of transcriptional changes occurred during nickel exposure, extensive transcriptional changes occurred during a second wave of transcription for which removal of nickel ions was essential. By uncovering a new category of transcriptional and epigenetic changes, which occur only after the termination of exposure, this study provides a novel understanding of the long-term deleterious consequences of nickel exposure on human health.

中文翻译：

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镍诱导的转录变化通过表观遗传重编程在暴露后持续存在。

背景镍是一种职业和环境毒物，与多种人类疾病相关，包括肺纤维化、支气管炎以及肺癌和鼻癌。我们早期的研究表明，镍暴露诱导的全基因组转录变化，即使在暴露终止后仍然存在，这可能是镍发病机制的基础。然而，驱动镍诱导的转录组持续变化的机制仍然难以捉摸。结果 为了阐明镍诱导的长期转录变化的机制，在本研究中，我们检查了人肺上皮细胞在镍暴露期间和暴露终止后的转录组和表观基因组。我们确定了两类持续差异表达的基因：(i) 在镍暴露期间差异表达的基因；(ii) 仅在暴露终止后差异表达的基因。有趣的是，> 85% 的镍诱导的基因表达变化仅在暴露终止后发生。我们还发现，在终止镍暴露后，激活组蛋白修饰 H3K4me3 发生了广泛的全基因组改变，这与暴露后基因表达的变化相吻合。此外，我们发现抑制性组蛋白修饰 H3K27me3 的显着暴露后改变。结论 我们的结果表明，虽然在镍暴露期间发生了适度的第一波转录变化，但在第二波转录期间发生了广泛的转录变化，其中镍离子的去除是必不可少的。