Effects of Zinc and DHA on the Epigenetic Regulation of Human Neuronal Cells

Abstract

Dietary intake of zinc and omega-3 fatty acids (DHA) have health benefits for a number of human diseases. However, the molecular basis of these health benefits remains unclear. Recently, we reported that zinc and DHA affect expression levels of histones H3 and H4 in human neuronal M17 cells. Here, using immunoblotting and densitometric analysis, we aimed to investigate the effect of zinc and DHA on post-translational modifications of histone H3 in M17 cells. In response to increase in zinc concentration, we observed increase in deacetylation, methylation and phosphorylation of H3 and decrease in acetylation. We also investigated the role of zinc in apoptosis, and found that zinc reduced the levels of the anti-apoptotic marker Bcl-2 while increasing the apoptotic marker caspase-3 levels, correlating with cell viability assays. Conversely, DHA treatment resulted in increase in acetylation of H3 and Bcl-2 levels and decrease in deacetylation, methylation, phosphorylation of H3 and caspase-3 levels, suggesting that DHA promotes gene expression and neuroprotection. Our novel findings show the opposing effects of zinc and DHA on the epigenetic regulation of human neuronal cells and highlight the potential benefit of dietary intake of DHA for management of neurodegenerative diseases.

Human neuronal cells: epigenetic aspects

“…Furthermore, during the zinc effect, caspase 3 expression increased, whereas Bcl-2 expression decreased. This observation was in complete contrast to the DHA effect, which demonstrates the highly neuroprotective properties that DHA offers in modulating the chromatin state and thus ameliorating the incidence of neurodegenerative diseases (25) . This research opens up new avenues to therapeutic potentials in treating neurodegenerative diseases such as AD.…”

“…The study effectively demonstrated that the DHA treatment induced H3K9 acetylation, including K9, K36, and K79 dimethylation, which decreased when treated with zinc. Alternatively, zinc promoted K4 and K27 dimethylation and T3 phosphorylation, which were shown to decrease upon DHA treatment (25) . This study provides insight into the underlying molecular mechanisms regarding dietary intake and its influence on epigenetic regulations, particularly histone PTMs in human neuronal cells.…”

“…In particular, certain foods contain bioactive components that can directly influence epigenetic machinery (24) . In a recent publication, the NeuroAllergy Research Laboratory demonstrated that zinc and DHA are involved in the modulation of histone H3 PTMs, including lysine (K) acetylation and dimethylation and threonine (T) phosphorylation within the M17 human neuroblastoma cells (25) . The study effectively demonstrated that the DHA treatment induced H3K9 acetylation, including K9, K36, and K79 dimethylation, which decreased when treated with zinc.…”

“…However, in the DHA effect (presence of zinc and DHA), histone expression was considerably upregulated (115) . In a subsequent study, Sadli et al (25) looked at the effects of zinc and DHA on the acetylation level of H3K9. It was discovered that H3K9 was significantly hypoacetylated with zinc and hyperacetylated with DHA.…”

Epigenetics and Metabolism

“…Similarly, docosahexaenoic acid decreased expression of HDAC1, HDAC2, and HDAC3 and induced global histone changes associated with transcriptional activation including H3-lysine-9 acetylation enrichment as well as depletion of H3-lysine-9 and -27 dimethylation in human neuronal cells. 159 Interestingly, docosahexaenoic acid was also shown to increase expression of H3 and H4 histones in the same cell line. 160 By contrast, palmitate induced HAT activity, and several genes that were modulated by lipotoxicity displayed altered patterns of histone modification in clonal β-cells.…”