Coordinated regulation of Nrf2 and histone H3 serine 10 phosphorylation in arsenite-activated transcription of the human heme oxygenase-1 gene

Abstract

Expression of the antioxidant gene heme oxygenase-1 (HO-1) is primarily induced through NFE2-related factor 2 (Nrf2)-mediated activation of the antioxidant response element (ARE). Gene transcription is coordinately regulated by transcription factor activity at enhancer elements and epigenetic alterations such as the posttranslational modification of histone proteins. However, the role of histone modifications in the Nrf2-ARE axis remains largely uncharacterized. The environmental contaminant arsenite is a potent inducer of both HO-1 expression and phosphorylation of histone H3 serine 10 (H3S10); therefore, we investigated the relationships between Nrf2 and H3S10 phosphorylation in arsenite-induced, ARE-dependent, transcriptional activation of the human HO-1 gene. Arsenite increased phosphorylation of H3S10 both globally and at the HO-1 promoter concomitantly with HO-1 transcription in human HaCaT keratinocytes. Conversely, arsenite-induced H3S10 phosphorylation and HO-1 expression was blocked by N-acetylcysteine (NAC), the c-Jun N-terminal kinase (JNK) inhibitor SP600125, and JNK knockdown (siJNK). Interestingly, ablation of arsenite-induced H3S10 phosphorylation by SP600125 or siJNK did not inhibit Nrf2 nuclear accumulation nor ARE binding, despite inhibiting HO-1 expression. In response to arsenite, binding of Nrf2 to the HO-1 ARE preceded phosphorylation of H3S10 at the HO-1 ARE. Furthermore, arsenite-mediated occupancy of phosphorylated H3S10 at the HO-1 ARE was decreased in Nrf2-deficient mouse embryonic fibroblasts. These results suggest the involvement of H3S10 phosphorylation in the Nrf2-ARE axis by proposing that Nrf2 may influence H3S10 phosphorylation at the HO-1 ARE and additional promoter regions. Our data highlights the complex interplay between Nrf2 and H3S10 phosphorylation in arsenite-activated HO-1 transcription.

Epigenomic reprogramming in inorganic arsenic-mediated gene expression patterns during carcinogenesis

“…Studies have suggested that arsenicinduced H3 phosphorylation might be responsible for the up-regulation of the oncogenes c-fos and c-jun (65). Most recently, Ray et al reported that iAs induces a coordinated regulation of Nrf2 and histone H3S10 phosphorylation, which activates the human heme oxygenase-1 gene (HMOX1) (52). These results reinforce the notion that iAs modulates gene expression by operating through the JNK and p38/Mpk2 kinase pathway to promote cancer.…”

“…These changes include increases in H3K9me2, H3K4me3, and H3S10, decreases in H2B ubiquitination, and either increases or decreases in H3K27me3 (47)(48)(49)(50)(51)(52). In addition, following iAs exposure in humans, blood cells exhibited an overall decrease in H3K9me3 and H3K9ac, with an increase in H3K9me2 (47,48).…”

miR-214 protects erythroid cells against oxidative stress by targeting ATF4 and EZH2

“…residues of Keap1 protein, resulting in the disruption of the contact between Keap1 and Nrf2 [11,[14][15][16]. Meanwhile, burgeoning evidence suggests that Nrf2 also targets mircroRNAs (miRNAs) that are involved in cell metabolism, adhesion, tumorigenesis and so on [17,18].…”

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).…”