Histone Methyltransferase MLL1 Mediates Oxidative Stress and Apoptosis upon Deoxynivalenol Exposure in the Intestinal Porcine Epithelial Cells

Abstract

Deoxynivalenol (DON), as a secondary metabolite of fungi, is continually detected in livestock feed and has a high risk to animals and humans. Moreover, pigs are very sensitive to DON. Recently, the role of histone modification has drawn people’s attention; however, few studies have elucidated how histone modification participates in the cytotoxicity or genotoxicity induced by mycotoxins. In this study, we used intestinal porcine epithelial cells (IPEC-J2 cells) as a model to DON exposure in vitro. Mixed lineage leukemia 1 (MLL1) regulates gene expression by exerting the role of methyltransferase. Our studies demonstrated that H3K4me3 enrichment was enhanced and MLL1 was highly upregulated upon 1 μg/mL DON exposure in IPEC-J2 cells. We found that the silencing of MLL1 resulted in increasing the apoptosis rate, arresting the cell cycle, and activating the mitogen-activated protein kinases (MAPKs) pathway. An RNA-sequencing analysis proved that differentially expressed genes (DEGs) were enriched in the cell cycle, apoptosis, and tumor necrosis factor (TNF) signaling pathway between the knockdown of MLL1 and negative control groups, which were associated with cytotoxicity induced by DON. In summary, these current results might provide new insight into how MLL1 regulates cytotoxic effects induced by DON via an epigenetic mechanism.

Sodium Butyrate Ameliorates Deoxynivalenol-Induced Oxidative Stress and Inflammation in the Porcine Liver via NR4A2-Mediated Histone Acetylation

“…Mycotoxin is tightly linked with the transcriptional processes involved in NR-mediated regulation . Increasing evidence have shown that NRs exert cardinal roles in regulating DON-induced OS and inflammatory genes through the recruitment of histone modifiers. , Apart from mediating inflammatory processes through the activation of IL-8 and the suppression of IL-4 in T-reg, , NR4A2 (encodes the NURR1 protein) also inhibits the transcription of the OS gene. , Sodium butyrate (NaBu) is a short-chain fatty acid that increases the average daily weight gain of piglets, provides energy for intestinal epithelium, plays an immunomodulatory role, and also regulates lipid metabolism in the liver and intestine . Notably, as a vital ligand of NR and a natural HDAC inhibitor, NaBu could alleviate DON-induced OS and inflammation. , Moreover, NaBu exerts anti-inflammatory effects by increasing the H3K9ac profiles at promoter regions of the pro-inflammatory genes and enhancing NR PPARA activation. − Therefore, we hypothesize NaBu resists DON-induced OS and the inflammatory response through histone acetylation recruited by NR4A2 .…”

From Challenge to Opportunity: Addressing Oxidative Stress in Animal Husbandry

“…The threat posed by mycotoxins, especially Deoxynivalenol (DON), is another area of concern. However, emerging research on histone modification in mycotoxin-induced cytotoxicity offers hope for potential interventions [ 7 ]. Polyphenols hold significant promise as feed additives for pigs; they may mitigate the oxidative stress and intestinal toxicity induced by DON [ 8 ].…”