title: Silver nanoparticle-induced hemoglobin decrease involves alteration of histone 3 methylation status.
abstract: Silver nanoparticles (nanosilver, AgNPs) have been shown to induce toxicity in vitro and in vivo; however, the molecular bases underlying the detrimental effects have not been thoroughly understood. Although there are numerous studies on its genotoxicity, only a few studies have investigated the epigenetic changes, even less on the changes of histone modifications by AgNPs. In the current study, we probed the AgNP-induced alterations to histone methylation that could be responsible for globin reduction in erythroid cells. AgNP treatment caused a significant reduction of global methylation level for histone 3 (H3) in erythroid MEL cells at sublethal concentrations, devoid of oxidative stress. The ChIP-PCR analyses demonstrated that methylation of H3 at lysine (Lys) 4 (H3K4) and Lys 79 (H3K79) on the β-globin locus was greatly reduced. The reduction in methylation could be attributed to decreased histone methyltransferase DOT-1L and MLL levels as well as the direct binding between AgNPs to H3/H4 that provide steric hindrance to prevent methylation as predicted by the all-atom molecular dynamics simulations. This direct interaction was further proved by AgNP-mediated pull-down assay and immunoprecipitation assay. These changes, together with decreased RNA polymerase II activity and chromatin binding at this locus, resulted in decreased hemoglobin production. By contrast, Ag ion-treated cells showed no alterations in histone methylation level. Taken together, these results showed a novel finding in which AgNPs could alter the methylation status of histone. Our study therefore opens a new avenue to study the biological effects of AgNPs at sublethal concentrations from the perspective of epigenetic mechanisms.
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; College of Biological and Environmental Engineering, Zhejiang University of Technology, Hangzhou, 310032, China.
authors: Yi
authors: Y
authors: Qian
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China.
authors: Jie
authors: J
authors: Zhang
authors: State Key Laboratory of Nonlinear Mechanics, Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, China.
authors: Qinglin
authors: Q
authors: Hu
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China.
authors: Ming
authors: M
authors: Xu
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China.
authors: Yue
authors: Y
authors: Chen
authors: State Key Laboratory of Nonlinear Mechanics, Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, China.
authors: Guoqing
authors: G
authors: Hu
authors: College of Biological and Environmental Engineering, Zhejiang University of Technology, Hangzhou, 310032, China. Electronic address: zhaomr@zjut.edu.cn.
authors: Meirong
authors: M
authors: Zhao
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China. Electronic address: sjliu@rcees.ac.cn.
authors: Sijin
authors: S
authors: Liu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056426:Genetic Loci; D006454:Hemoglobins; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D047468:Immunoprecipitation; D053768:Metal Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D008745:Methylation / Q000187:drug effects; D051379:Mice; D056004:Molecular Dynamics Simulation; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D012834:Silver / Q000494:pharmacology*; D055544:beta-Globins / Q000378:metabolism
chemical_list: D006454:Hemoglobins; D006657:Histones; D055544:beta-Globins; D012834:Silver; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase
keywords: Epigenetics; Hemoglobin; Histone; Methylation; Nanosilver; Transcription