基因敲除
海马结构
海马体
内分泌学
内科学
神经发生
甲基转移酶
信使核糖核酸
化学
生物
脱甲基酶
MAPK/ERK通路
细胞生物学
信号转导
甲基化
医学
细胞凋亡
生物化学
组蛋白
基因
作者
Yang Yang,Yue Feng,Yun Hu,Jie Liu,Hailing Shi,Ruqian Zhao
标识
DOI:10.1016/j.envpol.2021.117037
摘要
N6-methyladenosine (m6A) mRNA methylation plays a role in various brain functions. Exposure to chronic constant light (CCL) has been reported to impair cognition, yet whether the underlying mechanism involves m6A remains unknown. In this study, mice exposed to CCL for 3 weeks show impaired cognitive behavior, which was associated with increased m6A level in hippocampus. Accordingly, the m6A demethylase FTO was inhibited while the methyltransferases METTL3, METTL14 and WTAP, as well as the reader protein YTHDF2, were elevated in the hippocampus of CCL-exposed mice. CCL exposure significantly activated hippocampal expression of circadian regulator cryptochrome 1 and 2 (CRY1 and 2). Meanwhile, hippocampal neurogenesis was impaired with suppression of BDNF/TrκB/ERK pathway. To further delineate the signaling pathway and the role of m6A, we altered the expression of CRY1/2 in hippocampus neuron cells. CRY1/2 overexpression inhibited FTO and increased m6A levels, while CRY1/2 knockdown led to opposite results. Luciferase reporter analysis further confirmed CRY1/2-induced FTO suppression. Furthermore, FTO knockdown increased m6A on 3′UTR of TrκB mRNA, and decreased TrκB mRNA stability and TrκB protein expression, in a YTHDF2-dependent manner. These results indicate that CCL-activated CRY1/2 causes transcriptional inhibition of FTO, which suppresses TrκB expression in hippocampus via m6A-dependent post-transcriptional regulation and contributes to impaired cognitive behavior in mice exposed to constant light.
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