Sodium arsenite modulates histone acetylation, histone deacetylase activity and HMGN protein dynamics in human cells

Abstract

Extensive epidemiological data indicate that inorganic arsenic is associated with several types of human cancer. Nevertheless, the underlying mechanisms are poorly understood. Among its mode of action are the alterations on DNA methylation, which provoke aberrant gene expression. However, beyond DNA methylation, little is known about arsenic's effects on chromatin. In this study, we investigated the effects of sodium arsenite (NaAsO(2)) on global histone modifications and nucleosome-associated proteins. Our findings revealed that NaAsO(2) exposure significantly increases global histone acetylation. This effect was related to the inhibition of histone deacetylase (HDAC) activity because NaAsO(2) was able to inhibit HDACs comparable to the well-known HDAC inhibitor trichostatin A (TSA). Furthermore, analyses of the dynamic properties of the nucleosome-associated high mobility group N proteins demonstrate that NaAsO(2) elevates their mobility. Thus, our data suggest that NaAsO(2) induces chromatin opening by histone hyperacetylation due to HDAC inhibition and increase of the mobility of nucleosome-associated proteins. As the chromatin compaction is crucial for the regulation of gene expression as well as for genome stability, we propose that chromatin opening by NaAsO(2) may play a significant role to impart its genotoxic effects.

Influence of environmental exposure on human epigenetic regulation

“…Ramirez et al have shown that treatment with sodium arsenite in human hepatocarcinoma cells resulted in global increases in histone acetylation (Ramirez et al, 2008). In a substudy of a folate trial in highly arsenic-exposed Bangladeshi adults, total urinary arsenic levels were correlated with peripheral blood mononuclear cell global levels of histone H3 lysine 9 (K9) dimethylation and inversely correlated with histone H3-K9 acetylation, and sex led to opposite relationships between both urinary and water arsenic levels and global post-translational histone modifications (Chervona et al, 2012).…”

Incorporating epigenetic data into the risk assessment process for the toxic metals arsenic, cadmium, chromium, lead, and mercury: strategies and challenges

“…Arsenic exposure induces global and focal histone acetylation and methylation in human cell lines (Ramirez et al, 2008; Zhou et al, 2008, 2009; Jo et al, 2009; Chu et al, 2011). Arsenite modulates global H4K16Ac (Ramirez et al, 2008; Jo et al, 2009) as well as heterochromatic-specific H3K4me2 and euchromatic-specific H3K4me3 increases (Zhou et al, 2009).…”

“…Arsenite modulates global H4K16Ac (Ramirez et al, 2008; Jo et al, 2009) as well as heterochromatic-specific H3K4me2 and euchromatic-specific H3K4me3 increases (Zhou et al, 2009). Histone acetylation by arsenic is also gene specific; H3 phosphoacetylation by arsenic was associated with upregulation of caspase 10, apoptosis-related cysteine peptidase ( CASP10 ), and the proto-oncogenes C-Jun and C-Fos (Li et al, 2002, 2003).…”

“…Increases in H3K9 acetylation by arsenic in hepatocellular carcinoma cells was correlated with inhibition of HDAC activity (Ramirez et al, 2008). In human lung A549 cells, arsenic was shown to increase H3K9 di- and tri-methylation through increased expression of the H3K9 methyltransferase G9a; however there was no change in expression of lysine (K)-specific demethylase 3A (JHDM2A), the major demethylase involved in H3K9 dimethylation (Zhou et al, 2008).…”

Quantitative Mass Spectrometry Reveals Changes in Histone H2B Variants as Cells Undergo Inorganic Arsenic-Mediated Cellular Transformation

“…A number of studies have demonstrated that iAs exposure induces global and gene-specific post-translational histone modifications such as reduction of acetylation in histone H3 and H4: loss of H4Lys 16 10 and H2AX phosphorylation, and decreases in H2B ubiquitination (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26).…”