The Effect of Nickel on Gene Expression and Global Histone Marks

• Main Author: Arita, Adriana G
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01.01.2011
• Subjects: Environmental Health; Surgery
• ISBN: 9781267048547; 1267048549

Occupational exposure to nickel is associated with a high risk for developing lung and nasal cancers. However, the exact mechanism(s) of nickel-induced carcinogenesis is not known and has been the subject of numerous experimental and epidemiological investigations. Nickel compounds are not mutagenic, but are rather thought to induce silencing of tumor suppressor and senescence genes via epigenetic mechanisms. For my dissertation work I applied genomic approaches to further understand the effect of nickel exposure on gene expression and global histone marks in both in vitro and in vivo systems. First, we mapped the effect of nickel in vitro on H3K4me3 in the genome of peripheral blood mononuclear cells (PBMCs) using ChIP-Sequencing technology and correlated this with the in vitro gene expression changes induced by exposure to nickel. We found that the H3K4me3 mark maps near the transcription start site (TSS) of a number of nickel-induced genes, suggesting a mechanism by which the expression of nickel-induced genes is epigenetically modulated by H3K4me3 and/or other epigenetic marks. Additionally, we found that exposure to nickel increases H3K4me3 deposition and distribution in nickel-induced genes. Second, we examined the alterations in global histone marks and gene expression profiles in a human population occupationally exposed to nickel. We found that global levels of H3K4me3 were elevated, while global levels of H3K9me2 decreased in PBMCs of subjects with occupational exposure to nickel. Global levels of H3K4me3 were positively and global levels of H3K9ac were negatively associated with urinary nickel. Furthermore, we also found that the levels of global H3K4me3, H3K9me2, and H3K9ac in PBMCs were constant within subjects over time. We found 31 genes whose gene expression is changed in PBMCs of subjects with high occupational exposure to nickel compared with subjects with much lower environmental exposure. Nickel-induced genes associated with H3K4me3 were also identified. Last, a genome-wide deletion mutant screen was carried out to identify cellular factors and pathways affected by nickel sulfate in Saccharomyces cerevisiae. Here, genomic approaches, including Affymetrix GeneChip, ChIP-Sequencing, and a yeast deletion library, were used to identify plausible biomarkers of exposure to nickel.