Identification of histone acetylation modification sites in the striatum of subchronically manganese-exposed rats.

Aim: To explore the specific histone acetylation sites and oxidative stress-related genes that are associated with the pathogenesis of manganese toxicity. Methods: We employed liquid chromatography-tandem mass spectrometry and bioinformatics analysis to identify acetylated proteins in the striatum of subchronic manganese-intoxicated rats. Results: We identified a total of 12 differentially modified histone acetylation sites: H3K9ac, H3K14ac, H3K18ac, H3K56ac and H3K79ac were upregulated and H3K27ac, H3K36ac, H4K91ac, H4K79ac, H4K31ac, H2BK16ac and H2BK20ac were downregulated. Additionally, we found that CAT, SOD1 and SOD2 might be epigenetically regulated and involved in the pathogenesis of manganism. Conclusion: This study identified histone acetylation sites and oxidative stress-related genes associated with the pathogenesis of manganese toxicity, and these findings are useful in the search for potential epigenetic targets for manganese toxicity.

Histone demethylase JHDM2A participates in the repair of arsenic-induced DNA damage in L-02 cells by regulating DDB2.

Arsenic is widely present in nature and is a class I carcinogen confirmed by the World Health Organization and the International Agency for Research on Cancer. The liver is responsible for biotransformation in the body and is one of the major organs where arsenic accumulates in the body, but the mechanisms of arsenic-induced abnormal DNA damage repair pathways in the liver are still unclear. Recent studies have revealed that epigenetic mechanisms play an important role in arsenic-induced lesions. In this study, an in vitro model was established using human normal hepatocytes L-02 to investigate the mechanism of the specific demethylase JHDM2A of H3K9me2 in the repair of arsenic-induced DNA damage in L-02 cells. The results showed that with the increase of arsenic concentrations, the extent of DNA damage in L-02 cells showed an increasing trend and total intracellular H3K9me2 expression was downregulated. In addition, the enrichment level of H3K9me2 in the promoter region of DBB2, a key factor of nucleotide repair (NBR), increased, while protein and mRNA expression levels showed a decreasing trend. Thereafter, we overexpressed and repressed JHDM2A and found a close association between JHDM2A and arsenic-induced DNA damage. DDB2 protein and mRNA expression was downregulated with JHDM2A overexpression and upregulated with JHDM2A repression, while DBB2 promoter region H3K9me2 enrichment levels remained at a high level, although they were affected after JHDM2A overexpression or knockdown to some extent. These results suggest a potential mechanism by which JHDM2A may regulate DDB2 gene expression, participate in the NBR process, and play a role in arsenic-induced DNA damage in L-02 cells, which is not the result of JHDM2A exerting demethylation on H3K9me2 in the DDB2 promoter region. Our results provided an epigenetic mechanism for endemic arsenicosis, as well as a scientific basis for potential prevention and control measures.

Curcumin protects against manganese-induced neurotoxicity in rat by regulating oxidative stress-related gene expression via H3K27 acetylation.

Long-term manganese exposure causes a neurodegenerative disorder referred to as manganese poisoning, but the mechanism remains unclear and no specific treatment is available. Oxidative stress is widely recognised as one of the main causes of manganese-induced neurotoxicity. In recent years, the role of histone acetylation in neurodegenerative diseases has been widely concerned. curcumin is a natural polyphenol compound extracted from the rhizome of turmeric and exhibits both antioxidant and neuroprotective properties. Therefore, we aimed to investigate whether and how curcumin protects against manganese-induced neurotoxicity from the perspective of histone acetylation, based on the reversibility of histone acetylation modification. In this study, rats were treated with or without curcumin and subjected to long-term manganese exposure. Results that treatment of manganese decreased the protein expression of H3K18 acetylation and H3K27 acetylation at the promoters of oxidative stress-related genes and inhibited the expression of these genes. Nevertheless, curcumin increased the H3K27 acetylation level at the manganese superoxide dismutase (SOD2) gene promoter and promoted the expression of SOD2 gene. Oxidative damage in the rat striatum as well as learning and memory dysfunction were ameliorated after curcumin treatment. Taken together, our results suggest that the regulation of oxidative stress by histone acetylation may be a key mechanism of manganese-induced neurotoxicity. In addition, curcumin ameliorates Mn-induced neurotoxicity may be due to alleviation of oxidative damage mediated by increased activation of H3K27 acetylation at the SOD2 gene promoter.

The role of H3K9me2-regulated base excision repair genes in the repair of DNA damage induced by arsenic in HaCaT cells and the effects of Ginkgo biloba extract intervention.

Arsenic is an established human carcinogen that can induce DNA damage; however, the precise mechanism remains unknown. Histone modification is of great significance in chemical toxicity and carcinogenesis. To investigate the role of histone H3K9me2 in arsenic-induced DNA damage, HaCaT cells were exposed to sodium arsenite in this study, and the results showed that the enrichment level of H3K9me2 at the N-methylated purine-DNA-glycosylase (MPG), X-ray repair cross-complementary gene 1 (XRCC1), and polyadenylate diphosphate ribose polymerase-1 (PARP1) promoter regions of base-excision repair (BER) genes was increased, which inhibited the expression of these BER genes, thereby inhibiting the repair of DNA damage and aggravating the DNA damage. Furthermore, the molecular mechanism by which H3K9me2 participates in the BER repair of arsenic-induced DNA damage was verified based on functional loss and gain experiments. In addition, Ginkgo biloba extract can upregulate the expression of MPG, XRCC1, and PARP1 and ameliorate cell DNA damage by reducing the enrichment of H3K9me2 at repair gene promoter regions.

Histone demethylase JHDM2A regulates H3K9 dimethylation in response to arsenic-induced DNA damage and repair in normal human liver cells.

Long-term arsenic exposure is a worldwide public health problem that causes serious harm to human health. The liver is the main target organ of arsenic toxicity; arsenic induces disruption of the DNA damage repair pathway, but its mechanisms remain unclear. In recent years, studies have found that epigenetic mechanisms play an important role in arsenic-induced lesions. In this study, we conducted experiments in vitro using normal human liver cells (L-02) to explore the mechanism by which the histone demethylase JHDM2A regulates H3K9 dimethylation (me2) in response to arsenic-induced DNA damage. Our results indicated that arsenic exposure upregulated the expression of JHDM2A, downregulated global H3K9me2 modification levels, increased the H3K9me2 levels at the promoters of base excision repair (BER) genes (N-methylpurine-DNA glycosylase [MPG], XRCC1 and poly(ADP-ribose)polymerase 1) and inhibited their expression levels, causing DNA damage in cells. In addition, we studied the effects of overexpression and inhibition of JHDM2A and found that JHDM2A can participate in the molecular mechanism of arsenic-induced DNA damage via the BER pathway, which may not be involved in the BER process because H3K9me2 levels at the promoter region of the BER genes were unchanged following JHDM2A interference. These results suggest a potential mechanism by which JHDM2A can regulate the MPG and XRCC1 genes in the process of responding to DNA damage induced by arsenic exposure and can participate in the process of DNA damage repair, which provides a scientific basis for understanding the epigenetic mechanisms and treatments for endemic arsenic poisoning.