Nickel Ions Increase Histone H3 Lysine 9 Dimethylation and Induce Transgene Silencing

Chen, Haobin; Ke, Qingdong; Kluz, Thomas; Yan, Yan; Costa, Max

doi:10.1128/mcb.26.10.3728-3737.2006

Cited by 211 publications

(196 citation statements)

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“…In animal experiments, injection of particulate nickel compounds (nickel sulfide or nickel subsulfide) into mice induced formation of malignant fibrous histiocytomas and sarcomas, with the p16 and Fhit genes often found to be epigenetically silenced in these cancers (9,10). Additional studies have demonstrated that nickel exposure caused truncation of histone H2B and H2A as well as global alterations of a variety of histone modifications, such as histone acetylation, methylation, phosphorylation, and ubiquitination (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). However, the underlying mechanisms responsible for these nickel-induced epigenetic alterations are poorly understood.…”

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confidence: 99%

Nickel Ions Inhibit Histone Demethylase JMJD1A and DNA Repair Enzyme ABH2 by Replacing the Ferrous Iron in the Catalytic Centers

Chen

Giri

Zhang

et al. 2010

Journal of Biological Chemistry

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Iron-and 2-oxoglutarate-dependent dioxygenases are a diverse family of non-heme iron enzymes that catalyze various important oxidations in cells. A key structural motif of these dioxygenases is a facial triad of 2-histidines-1-carboxylate that coordinates the Fe(II) at the catalytic site. Using histone demethylase JMJD1A and DNA repair enzyme ABH2 as examples, we show that this family of dioxygenases is highly sensitive to inhibition by carcinogenic nickel ions. We find that, with iron, the 50% inhibitory concentrations of nickel (IC 50 Nickel compounds are human respiratory carcinogens (1), causing a very high incidence of lung and nasal cancers in nickel refinery workers (2). Over 20 years ago, our group reported that cells phagocytosed particulate nickel compounds, and the dissolution of these particles inside of the cells generated high concentrations of free nickel ions in the cytoplasm and nucleus (3). Using a dye that fluoresces when intracellular nickel ion binds to it, we showed that both soluble and insoluble nickel compounds were able to elevate the levels of nickel ions in the cytoplasmic and nuclear compartments (4). A strong correlation was found between the uptake of particulate nickel compounds by cells and subsequent cell transformation (5), suggesting that intracellular nickel ion concentration is a major determinant of toxicity and carcinogenicity of nickel compounds. Identifying the intracellular targets of nickel ions is therefore crucial to understand the underlying mechanism for the carcinogenic effects of nickel compounds.Silencing of tumor suppressor gene(s) by epigenetic mechanisms represents one of the potential mechanisms of nickel carcinogenesis. Epigenetic events, which include DNA methylation and histone modifications, are ubiquitously involved in the regulation of gene expression. By using a transgenic cell model with the target gene placed near heterochromatin, we were the first to demonstrate that nickel exposure caused a very high frequency of transgene silencing by increasing DNA methylation and repressive histone marks at the promoter of the silenced transgene (6 -8). In animal experiments, injection of particulate nickel compounds (nickel sulfide or nickel subsulfide) into mice induced formation of malignant fibrous histiocytomas and sarcomas, with the p16 and Fhit genes often found to be epigenetically silenced in these cancers (9,10). Additional studies have demonstrated that nickel exposure caused truncation of histone H2B and H2A as well as global alterations of a variety of histone modifications, such as histone acetylation, methylation, phosphorylation, and ubiquitination (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). However, the underlying mechanisms responsible for these nickel-induced epigenetic alterations are poorly understood. In our recent study, we reported that nickel increases the global levels of mono-and di-methylated histone H3 lysine 9 (H3K9me1 and H3K9me2) not by affecting histone methyltransferases but rather by inhibiting a group of unidentified iron-and...

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confidence: 99%

Nickel Ions Inhibit Histone Demethylase JMJD1A and DNA Repair Enzyme ABH2 by Replacing the Ferrous Iron in the Catalytic Centers

Chen

Giri

Zhang

et al. 2010

Journal of Biological Chemistry

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134

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“…Intriguingly, Ni-induced silencing of gpt and increased H3K9me2 levels occurred only when the transgene was integrated near a heterochromatic region (13,14,21). This suggests that Ni could induce H3K9me2 spreading.…”

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“…In the transgenic gpt+ Chinese hamster V79-derived G12 cells, silencing of the bacterial xanthine-guanine phosphoribosyltransferase (gpt) transgene following Ni exposure is associated with an increase in H3K9me2 and a decrease in H3 and H4 acetylation at the promoter and coding regions (13,14,21). Intriguingly, Ni-induced silencing of gpt and increased H3K9me2 levels occurred only when the transgene was integrated near a heterochromatic region (13,14,21).…”

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confidence: 99%

“…However, how H3K9me2 domains are maintained and the consequences of aberrant domain disruption are poorly understood. An important clue toward understanding the H3K9me2 domains comes from studies that investigated silencing of a transgene following the exposure of cells to nickel (13,14). Nickel compounds are environmental carcinogens that cause a multitude of human health risks including allergic dermatitis, bronchitis, pulmonary fibrosis, pulmonary edema, diseases of the kidney and cardiovascular system, and lung and nasal cancers (15,16).…”

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Epigenetic dysregulation by nickel through repressive chromatin domain disruption

Jose

Jagannathan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Investigations into the genomic landscape of histone modifications in heterochromatic regions have revealed histone H3 lysine 9 dimethylation (H3K9me2) to be important for differentiation and maintaining cell identity. H3K9me2 is associated with gene silencing and is organized into large repressive domains that exist in close proximity to active genes, indicating the importance of maintenance of proper domain structure. Here we show that nickel, a nonmutagenic environmental carcinogen, disrupted H3K9me2 domains, resulting in the spreading of H3K9me2 into active regions, which was associated with gene silencing. We found weak CCCTC-binding factor (CTCF)-binding sites and reduced CTCF binding at the Ni-disrupted H3K9me2 domain boundaries, suggesting a loss of CTCF-mediated insulation function as a potential reason for domain disruption and spreading. We furthermore show that euchromatin islands, local regions of active chromatin within large H3K9me2 domains, can protect genes from H3K9me2-spreadingassociated gene silencing. These results have major implications in understanding H3K9me2 dynamics and the consequences of chromatin domain disruption during pathogenesis.insulator | nickel toxicity | nickel carcinogenesis

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“…More recent studies have also reported heavy metal-associated histone modifications and chromatin organization [72,73]. Specifically, nickel ions induce the silencing of the gpt transgene in G12 Chinese hamster cells by increasing histone H3K9 dimethylation via inhibition of H3K9 demethylation [73].…”

Section: Heavy Metals-mentioning

confidence: 99%

Epigenetic reprogramming and imprinting in origins of disease

Tang

2007

Rev Endocr Metab Disord

217

134

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The traditional view that gene and environment interactions control disease susceptibility can now be expanded to include epigenetic reprogramming as a key determinant of origins of human disease. Currently, epigenetics is defined as heritable changes in gene expression that do not alter DNA sequence but are mitotically and trans-generationally inheritable. Epigenetic reprogramming is the process by which an organism's genotype interacts with the environment to produce its phenotype and provides a framework for explaining individual variations and the uniqueness of cells, tissues, or organs despite identical genetic information. The main epigenetic mediators are histone modification, DNA methylation, and non-coding RNAs. They regulate crucial cellular functions such as genome stability, X-chromosome inactivation, gene imprinting, and reprogramming of non-imprinting genes, and work on developmental plasticity such that exposures to endogenous or exogenous factors during critical periods permanently alter the structure or function of specific organ systems. Developmental epigenetics is believed to establish "adaptive" phenotypes to meet the demands of the later-life environment. Resulting phenotypes that match predicted later-life demands will promote health, while a high degree of mismatch will impede adaptability to later-life challenges and elevate disease risk. The rapid introduction of synthetic chemicals, medical interventions, environmental pollutants, and lifestyle choices, may result in conflict with the programmed adaptive changes made during early development, and explain the alarming increases in some diseases. The recent identification of a significant number of epigenetically regulated genes in various model systems has prepared the field to take on the challenge of characterizing distinct epigenomes related to various diseases. Improvements in human health could then be redirected from curative care to personalized, preventive medicine based, in part, on epigenetic markings etched in the "margins" of one's genetic make-up. NIH Public Access Author ManuscriptRev Endocr Metab Disord. Author manuscript; available in PMC 2014 June 13. Epigenetics meets genetics in disease susceptibilityIn the past, susceptibility of disease was believed to be determined solely by inheritable information carried on the primary sequence of the DNA. Individuals are endowed with different genotypes that dictate how they respond to endogenous factors such as development cues, hormones, and cytokines or to exogenous influences, including nutrient availability, infection, physical activities, social behavior, and other environmental factors. Over time, these responses form the basis of genetic variability to disease susceptibility. Aberrant changes in linear DNA sequence result in mutations, deletions, gene fusion, tandem duplications, or gene amplifications causing dysregulation of gene expression that underlies the genesis of disease [1][2][3][4][5][6][7]. Recently, however, it has become clear that epigenetic disr...

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Nickel Ions Increase Histone H3 Lysine 9 Dimethylation and Induce Transgene Silencing

Cited by 211 publications

References 35 publications

Nickel Ions Inhibit Histone Demethylase JMJD1A and DNA Repair Enzyme ABH2 by Replacing the Ferrous Iron in the Catalytic Centers

Nickel Ions Inhibit Histone Demethylase JMJD1A and DNA Repair Enzyme ABH2 by Replacing the Ferrous Iron in the Catalytic Centers

Epigenetic dysregulation by nickel through repressive chromatin domain disruption

Epigenetic reprogramming and imprinting in origins of disease

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