Epigenetic dysregulation by nickel through repressive chromatin domain disruption (original) (raw)
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Nickel Ions Increase Histone H3 Lysine 9 Dimethylation and Induce Transgene Silencing
Molecular and Cellular Biology, 2006
We have previously reported that carcinogenic nickel compounds decreased global histone H4 acetylation and silenced the gpt transgene in G12 Chinese hamster cells. However, the nature of this silencing is still not clear. Here, we report that nickel ion exposure increases global H3K9 mono- and dimethylation, both of which are critical marks for DNA methylation and long-term gene silencing. In contrast to the up-regulation of global H3K9 dimethylation, nickel ions decreased the expression and activity of histone H3K9 specific methyltransferase G9a. Further investigation demonstrated that nickel ions interfered with the removal of histone methylation in vivo and directly decreased the activity of a Fe(II)-2-oxoglutarate-dependent histone H3K9 demethylase in nuclear extract in vitro. These results are the first to show a histone H3K9 demethylase activity dependent on both iron and 2-oxoglutarate. Exposure to nickel ions also increased H3K9 dimethylation at the gpt locus in G12 cells an...
Molecular and cellular biology, 1995
A transgenic gpt+ Chinese hamster cell line (G12) was found to be susceptible to carcinogenic nickel-induced inactivation of gpt expression without mutagenesis or deletion of the transgene. Many nickel-induced 6-thioguanine-resistant variants spontaneously reverted to actively express gpt, as indicated by both reversion assays and direct enzyme measurements. Since reversion was enhanced in many of the nickel-induced variant cell lines following 24-h treatment with the demethylating agent 5-azacytidine, the involvement of DNA methylation in silencing gpt expression was suspected. This was confirmed by demonstrations of increased DNA methylation, as well as by evidence indicating condensed chromatin and heterochromatinization of the gpt integration site in 6-thioguanine-resistant cells. Upon reversion to active gpt expression, DNA methylation and condensation are lost. We propose that DNA condensation and methylation result in heterochromatinization of the gpt sequence with subsequent...
Alterations of histone modifications and transgene silencing by nickel chloride
Carcinogenesis, 2006
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.
Heterochromatinization as a Potential Mechanism of Nickel-Induced Carcinogenesis
Biochemistry, 2009
Epigenetics refers to heritable patterns of gene expression that do not depend on alterations of the genomic DNA sequence. Nickel compounds have demonstrated carcinogenicity without any associated mutagenesis, suggesting that its mechanism of carcinogenesis is epigenetic in nature. One such potential mechanism is the heterochromatinization of chromatin within a region of the genome containing a gene sequence, inhibiting any further molecular interactions with that underlying gene sequence and effectively inactivating that gene. We report here the observation, by atomic force microscopy and circular dichroism spectropolarimetry, that nickel ion (Ni 2+) condenses chromatin to a greater extent than the natural divalent cation of the cell, magnesium ion (Mg 2+). In addition, we use a model experimental system that incorporates a transgene, the bacterial xanthine guanine phosphoribosyl transferase gene (gpt) differentially near to, and far away from, a heterochromatic region of the genome, in two cell lines, the Chinese hamster V79-derived G12 and G10 cells, respectively, to demonstrate by DNase I protection assay that nickel treatement protects the gpt gene sequence from DNase I exonuclease digestion in the G12 cells, but not in the G10 cells. We conclude that condensation of chromatin by nickel is a potential mechanism of nickel-mediated gene regulation.
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology, 2017
Nickel compounds are well-established human carcinogens with weak mutagenic activity. Histone methylation has been proposed to play an important role in nickel-induced carcinogenesis. Nicotinamide N-methyltransferase (NNMT) decreases histone methylation in several cancer cells by altering the cellular ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH). However, the role of NNMT in nickel-induced histone methylation remains unclear. BEAS-2B cells were exposed to different concentrations of nickel chloride (NiCl2) for 72 h or 200 μM NiCl2 for different time periods. Histone H3 on lysine 9 (H3K9) mono-, di-, and trimethylation and NNMT protein levels were measured by western blot analysis. Expressions of NNMT mRNA and the H3k9me2-associated genes, mitogen-activated protein kinase 3 (MAP2K3) and dickkopf1 (DKK1), were determined by qPCR analysis. The cellular ratio of nicotinamide adenine dinucleotide (NAD+) to reduced NAD (NADH) and SAM/SAH ratio were determined. Expos...
Chemical Research in Toxicology, 2003
We have demonstrated previously that Ni(II) binds to the C-terminal-TESHHKAKGK motif of isolated bovine histone H2A. At physiological pH, the bound Ni(II) assists in hydrolysis of the E-S peptide bond in this motif that results in a cleavage of the terminal octapeptide SHHKAKGK off the histone's C-tail. To test if the hydrolysis could also occur in living cells, we cultured CHO (Chinese hamster ovary), NRK-52 (rat renal tubular epithelium), and HPL1D (human lung epithelium) cells with 0.1-1 mM Ni(II) for 3-7 days. As found by gel electrophoresis, Western blotting, and liquid chromatography/mass spectrometry, histones extracted from the cells contained a new fraction of histone H2A lacking the terminal octapeptide (q-H2A). The abundance of q-H2A increased with Ni(II) concentration and exposure time. It can be anticipated that the truncation of histone H2A may alter chromatin structure and affect gene expression. The present results provide evidence for novel mechanisms of epigenetic effects of Ni(II) that may be involved in nickel toxicity and carcinogenesis.
Molecular Mechanisms of Nickel Carcinogenesis
Annual Review of Pharmacology and Toxicology, 1991
Humans are exposed to carcinogenic nickel (Ni) compounds both occupationally and environmentally. In this paper, molecular mechanisms of nickel carcinogenesis are considered from the point-of-view of the uptake of nickel sulfide particles in cells, their dissolution and their effects on heterochromatin. Molecular mechanisms by which nickel induces gene silencing, DNA hypermethylation and inhibition of histone acetylation, will be discussed.
Nickel compounds are established human carcinogens. Their carcinogenic activity is consistently related to the ability of Ni(II) to access chromatin and cause multiple types of cellular nuclear damage via direct or indirect mechanisms. The mechanistic concepts proposed for nickel carcinogenesis include promutagenic DNA damage [1,2], epigenetic effects in chromatin [3-5], and impairment of DNA repair [6]. The core histone octamer (formed by two copies of histones H3, H4, H2A and H2B) together with the linker histone H1, package eukaryotic DNA into repeating nucleosomal units that are folded into higher order chromatin fibres. Due to its abundance inside the cell nucleus this histone octamer is a good target for nickel binding. We focused our interest on histone H4, first of all because it has been reported that nickel(II) is a potent suppressor of histone H4 acetylation, in both yeast and mammalian cells [7], and this may lead to transcription errors and subsequent DNA modifications [8]. Secondly, an anchoring binding site for nickel ion on the terminal part of this protein, specifically histidine H18, is close to sites for post-translational modifications involved in nickel toxicity. All this evidence points to the H4 tail as a candidate for Ni(II) binding on the histone octamer, and the study of its N-terminal tail as a model for metal coordination can supply useful information in the effort of unveiling the mechanisms of nickel carcinogenesis. We previously reported, by potentiometric and spectroscopic (NMR, Uv-Vis, CD) studies, about the interaction of Ni(II) with minimal models of the H4 tail: the two peptides with 6 amino acids Ac-AKRHRK-Am and with 22 amino acids Ac-SGRGKGGKGLGKGGAKRHRK VL-Am, respectively [9-11]. Here we present our recent results on the coordination ability of Ni(II) to the N-terminal tail of histone H4, the 30-amino acid peptide Ac-SGRGKGGKGLGKGGAKRH18RKVLRDNIQGITAm, achieved by the use of multidimensional NMR spectroscopy.
Nickel binding sites in histone proteins: Spectroscopic and structural characterization
Coordination Chemistry Reviews, Volume 257, Issues 19–20, October 2013, Pages 2737-2751
Nickel compounds are included among human carcinogens, though the molecular events related to them are not yet completely known. It has been proposed that the basic element, in the mechanism of carcinogenesis exerted by nickel, is connected to its binding within the cell nucleus. DNA can weakly bind Ni(II), thus the nuclear proteins, in particular histones proteins which are abundantly present, could be important targets for Ni(II) ions. The present review describes the interactions of nickel with histone H4, core tetramer (H3-H4)2 and several peptide fragments which have been selected as possible candidates for specific binding sites in the histone octamer. The collected results allowed us to propose several mechanisms for nickel-induced damage triggering from metal coordination, including structural changes of histone proteins, as well as nucleobase oxidation and sequence-specific histone hydrolysis.
Molecular Mechanisms in Nickel Carcinogenesis: Modeling Ni(II) Binding Site in Histone H4
Environmental Health Perspectives, 2002
Ni(II) compounds are well known as human carcinogens, though the molecular events which are responsible for this are not yet fully understood. It has been proposed that the binding of N(II) ions within the cell nucleus is a crucial element in the mechanism of carcinogenesis. The most abundant proteins in the cell nucleus are histones, and this makes them the prime candidates for this role. This article is a review of our recent studies of histone H4 models of Ni(II) binding. We analyzed the sequence of the N-terminal tail of the histone H4, Ac-SGRGKGGKGLGKGG AKRH 18 RKVL-Am, for Ni(II) binding. This site has been proposed mainly because of the potent inhibitory effect of Ni(II) on the acetylation of lysine residues near the histidine H 18 , and also because of the accessibility of the H4 tail in the histone octamer. Combined potentiometric and spectroscopic studies showed that the histidine 18 acted as an anchoring binding site for metal ions in the peptide investigated. Comparison with the results for Cu(II) binding are also reported. The results allowed us to propose that the binding of Ni(II) is able to promote a secondary structure with organized side-chain orientation on the N-terminal tail of histone H4.