Department of Pediatrics, TongJi Hospital, TongJi Medical College, Huazhong University of Science and Technology, Huazhong, China.
Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, USA.
Sci Rep. 2018 Nov 15;8(1):16838. doi: 10.1038/s41598-018-34899-2.
Chronic exposure to environmental heavy metals is a worldwide health concern. It is acknowledged to be an important cause of lower respiratory tract damage in children. However, the molecular mechanisms underlying the heavy metal-induced cellular stress/toxicity are not completely understood. Small non-coding RNAs (sncRNAs), such as microRNAs (miRNA) and more recently identified tRNA-derived RNA fragments (tRFs), are critical to the posttranscriptional control of genes. We used deep sequencing to investigate whether cellular sncRNA profiles are changed by environmental heavy metals. We found that the treatment of arsenite, an important groundwater heavy metal, leads to abundant production of tRFs, that are ~30 nucleotides (nts) long and most of which correspond to the 5'-end of mature tRNAs. It is unlikely for these tRFs to be random degradation by-products, as the type of induced tRFs is heavy metal-dependent. Three most inducible tRFs and their roles in arsenite-induced cellular responses were then investigated. We identified that p65, an important transcription factor belonging to NF-κB family and also a key factor controlling inflammatory gene expression, is a regulated target of a tRF derived from 5'-end of mature tRNA encoding AlaCGC (tRF5-AlaCGC). tRF5-AlaCGC activates p65, subsequently leading to enhanced secretion of IL-8 in arsenite response. In this study, we also identified that endonuclease Dicer and angiogenin temporally control the induction of tRF5-AlaCGC, providing an insight into the control of tRF biogenesis and subsequently the prevention of cellular damage.
慢性暴露于环境重金属是一个全球性的健康问题。它被认为是儿童下呼吸道损伤的重要原因。然而，重金属诱导的细胞应激/毒性的分子机制尚不完全清楚。小非编码 RNA（sncRNA），如 microRNA（miRNA）和最近鉴定的 tRNA 衍生的 RNA 片段（tRFs），对于基因的转录后调控至关重要。我们使用深度测序来研究环境重金属是否会改变细胞 sncRNA 谱。我们发现，亚砷酸盐（一种重要的地下水重金属）的处理导致大量 tRFs 的产生，这些 tRFs 长约 30 个核苷酸（nt），并且大多数与成熟 tRNA 的 5'-端相对应。这些 tRFs 不太可能是随机降解的副产物，因为诱导的 tRF 类型是重金属依赖性的。然后研究了三种最可诱导的 tRF 及其在亚砷酸盐诱导的细胞反应中的作用。我们鉴定出 p65，一种属于 NF-κB 家族的重要转录因子，也是控制炎症基因表达的关键因素，是来自成熟 tRNA 编码 AlaCGC（tRF5-AlaCGC）的 5'-端的 tRF 的调节靶标。tRF5-AlaCGC 激活 p65，随后导致 IL-8 在亚砷酸盐反应中的分泌增强。在这项研究中，我们还鉴定出内切酶 Dicer 和血管生成素在时间上控制 tRF5-AlaCGC 的诱导，这为 tRF 生物发生的控制以及随后的细胞损伤预防提供了深入了解。
