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Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers
Published on: September 20, 2018
Alterations of histone modifications and transgene silencing by nickel chloride
Qingdong Ke1, Todd Davidson, Haobin Chen
1Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.
Abstract:
Although it has been well established that insoluble nickel compounds are potent carcinogens and soluble nickel compounds are less potent, the mechanisms remain unclear. Nickel compounds are weakly mutagenic, but cause epigenetic effects in cells. Previous studies have shown that insoluble nickel compounds enter cells by phagocytosis and silence gene expression, but the entry of soluble nickel compounds and their effects on gene silencing have not been well studied. Here, we have demonstrated, using a dye that fluoresces when nickel ions bind, that soluble nickel compounds were taken up by cells. Nickel ions localized initially in the cytoplasm, but later entered the nucleus and eventually silenced a transgene. In addition, we described three major changes in histone modification of cells exposed to soluble nickel compounds: (i) loss of acetylation of H2A, H2B, H3 and H4; (ii) increases of H3K9 dimethylation; and (iii) substantial increases of the ubiquitination of H2A and H2B. These effects were observed at nickel exposure conditions that had minimum effects on cell cytotoxicity. Moreover, we demonstrated that nickel-induced transgene silencing was associated with similar changes of histone modifications in their nuclesomes. This study is the first to show that nickel compounds increase histone ubiquitination in cells. These new findings will further our understanding of the epigenetic mechanisms of nickel-mediated carcinogenesis.
Insights
Soluble nickel compounds enter cells and alter histone modifications, leading to gene silencing. This study reveals nickel
Area of Science:
- Environmental toxicology
- Epigenetics
- Molecular biology
Background:
- Insoluble nickel compounds are known carcinogens, but mechanisms of soluble nickel compounds are unclear.
- Nickel compounds can cause epigenetic effects, including gene silencing.
- Cellular uptake and effects of soluble nickel compounds require further investigation.
Purpose of the Study:
- To investigate the cellular uptake and epigenetic effects of soluble nickel compounds.
- To elucidate the mechanisms of gene silencing induced by soluble nickel.
- To identify specific histone modification changes associated with soluble nickel exposure.
Main Methods:
- Utilized a nickel-binding fluorescent dye to track cellular uptake of soluble nickel compounds.
- Observed nickel ion localization within cells using microscopy.
- Analyzed changes in histone modifications (acetylation, dimethylation, ubiquitination) via molecular techniques.
Main Results:
- Demonstrated cellular uptake and nuclear entry of soluble nickel ions.
- Identified nickel-induced loss of histone acetylation and increased H3K9 dimethylation.
- Showed substantial increases in H2A and H2B ubiquitination, linked to transgene silencing.
- Observed these epigenetic changes at non-cytotoxic nickel concentrations.
Conclusions:
- Soluble nickel compounds are taken up by cells and induce epigenetic alterations, including histone ubiquitination.
- Nickel-induced gene silencing is associated with specific histone modification changes.
- Findings provide new insights into the epigenetic mechanisms of nickel-mediated carcinogenesis.
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