Nickel-induced transcriptional changes persist post exposure through epigenetic reprogramming
Nickel-induced transcriptional changes persist post exposure through epigenetic reprogramming
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DOI：
10.1186/s13072-019-0324-3
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发表时间：
2019-12-19
影响因子：
3.9
通讯作者：
Cuddapah, Suresh
中科院分区：
文献类型：
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作者：
Jose, Cynthia C.;Wang, Zhenjia;Cuddapah, Suresh
镍是一种职业和环境毒物，与许多人类疾病有关，包括肺纤维化、支气管炎、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持续存在，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，本研究检测了镍暴露期间和暴露终止后人肺上皮细胞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）仅在暴露终止后才差异表达的基因。有趣的是，85%的镍诱导的基因表达变化只发生在暴露终止后。我们还发现，在镍暴露终止后，激活组蛋白修饰H3K4me3在全基因组范围内发生了广泛的改变，这与暴露后基因表达的变化相吻合。此外，我们发现抑制组蛋白修饰H3K27me3暴露后显著改变。我们的研究结果表明，虽然在镍暴露期间发生了适度的第一波转录变化，但在第二波转录中发生了广泛的转录变化，而镍离子的去除是必不可少的。通过揭示仅在接触终止后才发生的转录和表观遗传变化的新类别，本研究对镍接触对人体健康的长期有害后果提供了新的认识。
BackgroundNickel 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.ResultsTo 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.ConclusionOur 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.