Biology Direct
·
2024
·Vol. 19
·期 1
·1-17
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IF 5.7
Yu Zhengtao,Xia Ying,Li Jiameng,Jiang Junwen,Li You,Li Youjun,Wang Liu
Background Ischemia/reperfusion (I/R) injury is a severe brain disorder with currently limited effective treatments. This study aims to explore the role of N6-methyladenosine (m6A) modification and associated regulatory factors in I/R to identify potential therapeutic targets. Methods We utilized a middle cerebral artery occlusion (MCAO) rat model and SH-SY5Y cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to assess m6A levels and investigate the impact of METTL3 overexpression on long non-coding RNA (lncRNA) CRNDE expression. The effects of silencing lncRNA CRNDE on the interaction between YTHDC1 and ATG10 mRNA, as well as the stability of ATG10 mRNA, were evaluated. Additionally, apoptosis rates, pro-inflammatory and anti-inflammatory factor levels, ATG10 expression, and autophagic activity were analyzed to determine the effects of METTL3 . The reverse effects of YTHDC1 overexpression were also examined. Results MCAO rats and OGD/R-treated SH-SY5Y cells exhibited reduced m6A levels. METTL3 overexpression significantly inhibited lncRNA CRNDE expression. Silencing lncRNA CRNDE mitigated OGD/R-induced apoptosis and inflammation in SH-SY5Y cells, while enhancing autophagy and stabilizing ATG10 mRNA. METTL3 overexpression decreased cell apoptosis, reduced the levels of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and increased IL-10 secretion. Furthermore, METTL3 overexpression upregulated ATG10 expression and promoted autophagy. Conversely, lncRNA CRNDE overexpression negated these effects. Conclusion The inhibition of lncRNA CRNDE affects the interaction between YTHDC1 and ATG10 mRNA and stabilizes ATG10 mRNA, mediated by METTL3 overexpression. These findings suggest that targeting lncRNA CRNDE to reduce apoptosis, inhibit inflammation, increase ATG10 expression, and enhance autophagy could offer new therapeutic strategies for I/R injury.
研究领域:
神经科学
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分子生物学
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2024
·
IF 12.2
Lixiao Zhou,Renjie Li,Fu Wang,Ruiqi Zhou,Yinyin Xia,Xuejun Jiang,Shuqun Cheng,Fanghong Wang,Danyang Li,Jun Zhang,Lejiao Mao,Xuemei Cai,Hongyang Zhang,Jingfu Qiu,Xin Tian,Zhen Zou,Chengzhi Chen
Excessive exposure to metals in daily life has been proposed as an environmental risk factor for neurological disorders. Oxidative stress is an inevitable stage involved in the neurotoxic effects induced by metals, nevertheless, the underlying mechanisms are still unclear. In this study, we used arsenic as a representative environmental heavy metal to induce neuronal oxidative stress and demonstrated that both in vitro and in vivo exposure to arsenic significantly increased the level of N6-methyladenosine (m6A) by down-regulating its demethylase FTO. Importantly, the results obtained from FTO transgenic mice and FTO overexpressed/knockout cells indicated that FTO likely regulated neuronal oxidative stress by modulating activating transcription factor 3 (ATF3) in a m 6 A-dependent manner. We also identified the specific m6A reader protein, YTHDC1, which interacted with ATF3 and thereby affecting its regulatory effects on oxidative stress. To further explore potential intervention strategies, cerebral metabolomics was conducted and we newly identified myo-inositol as a metabolite that exhibited potential in protecting against arsenic-induced oxidative stress and cognitive dysfunction. Overall, these findings provide new insights into the importance of the FTO-ATF3 signaling axis in neuronal oxidative stress from an m 6 A perspective, and highlight a beneficial metabolite that can counteract the oxidative stress induced by arsenic.
研究领域:
神经科学
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毒理学
·
分子生物学
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代谢组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2025
·Vol. 16
·期 1
·1-19
·
IF 9.6
Chen Shengjun,Wang Yujie,Zhang Jinjin,Liu Bo,Liu Weili,Cao Guohong,Li Rongrong,Li Hongbo,Zhai Nailiang,Song Xiaodong,Zhang Songzi,Lv Changjun
Fibroblast-to-myofibroblast differentiation is the main cytopathologic characteristic of pulmonary fibrosis. However, its underlying molecular mechanism remains poorly understood. This study elucidated that the nuclear export of lncNONMMUT062668.2 (lnc668) exacerbated pulmonary fibrosis by activating fibroblast-to-myofibroblast differentiation. Mechanistic research revealed that histone H3K9 lactylation in the promoter region of the N6-methyladenosine (m 6 A) writer METTL3 was enriched to enhance METTL3 transcription, leading to the lnc668 m 6 A modification. Meanwhile, the m 6 A reader YTHDC1 recognized m 6 A-modified lnc668 and elevated the METTL3-mediated lnc668 modification. Subsequently, phase-separating YTHDC1 promoted the nuclear export of m 6 A-modified lnc668. In this process, the phase-separating YTHDC1 formed a nuclear pore complex with serine/arginine-rich splicing factor 3, Aly/REF export factor, and exportin-5 to assist the translocation of m 6 A-modified lnc668 from nucleus to cytoplasm. After nuclear export, lnc668 facilitated the translation and stability of its host gene phosphatidylinositol-binding clathrin assembly protein to activate fibroblast-to-myofibroblast differentiation, leading to the aggravation of pulmonary fibrosis, which also depended on YTHDC1 phase separation. This study first clarified that YTHDC1 phase separation is crucial for the m 6 A modification, nuclear export, and profibrotic role of lnc668 in exacerbating pulmonary fibrosis. These findings provide new insights into the nuclear export of cytoplasmic lncRNAs and identified potential targets for pulmonary fibrosis therapy.
研究领域:
分子生物学
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表观遗传学
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肺病学
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RNA生物学
✓ 已验证
DOI
PubMed
高影响因子
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