1. Deoxynivalenol induces m 6 A-mediated upregulation of p21 and growth arrest of mouse hippocampal neuron cells in vitro.
- Author
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Xu P, Zhao Y, Feng Y, Zhao M, and Zhao R
- Subjects
- Animals, Mice, RNA-Binding Proteins metabolism, RNA-Binding Proteins genetics, Cell Line, 3' Untranslated Regions genetics, Neurogenesis drug effects, RNA, Messenger metabolism, RNA, Messenger genetics, RNA Stability drug effects, Cell Cycle Checkpoints drug effects, Ribonucleoproteins metabolism, Ribonucleoproteins genetics, Methylation drug effects, Trichothecenes toxicity, Trichothecenes pharmacology, Hippocampus metabolism, Hippocampus drug effects, Hippocampus cytology, Neurons drug effects, Neurons metabolism, Cyclin-Dependent Kinase Inhibitor p21 metabolism, Cyclin-Dependent Kinase Inhibitor p21 genetics, Up-Regulation drug effects, Cell Proliferation drug effects
- Abstract
Hippocampal neurons maintain the ability of proliferation throughout life to support neurogenesis. Deoxynivalenol (DON) is a mycotoxin that exhibits brain toxicity, yet whether and how DON affects hippocampal neurogenesis remains unknown. Here, we use mouse hippocampal neuron cells (HT-22) as a model to illustrate the effects of DON on neuron proliferation and to explore underlying mechanisms. DON exposure significantly inhibits the proliferation of HT-22 cells, which is associated with an up-regulation of cell cycle inhibitor p21 at both mRNA and protein levels. Global and site-specific m
6 A methylation levels on the 3'UTR of p21 mRNA are significantly increased in response to DON treatment, whereas inhibition of m6 A hypermethylation significantly alleviates DON-induced cell cycle arrest. Further mechanistic studies indicate that the m6 A readers YTHDF1 and IGF2BP1 are responsible for m6 A-mediated increase in p21 mRNA stability. Meanwhile, 3'UTR of E3 ubiquitin ligase TRIM21 mRNA is also m6 A hypermethylated, and another m6 A reader YTHDF2 binds to the m6 A sites, leading to decreased TRIM21 mRNA stability. Consequently, TRIM21 suppression impairs ubiquitin-mediated p21 protein degradation. Taken together, m6 A-mediated upregulation of p21, at both post-transcriptional and post-translational levels, contributes to DON-induced inhibition of hippocampal neuron proliferation. These results may provide new insights for epigenetic therapy of neurodegenerative diseases., (© 2024. The Author(s).)- Published
- 2024
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