Cell and Bioscience
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2025
·Vol. 15
·期 1
·1-23
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IF 6.2
Ji Hao-Nan,Zhou Hai-Qian,Qie Jing-Bo,Lu Wen-Mei,Gao Hai-Tao,Wu Dan-Hong
Background The identification and intervention of Alzheimer’s Disease (AD) in its early-stage allows for the timely implementation of lifestyle modifications and therapeutic strategies. Although dysregulation of protein expression has been reported in the brain from AD patients and AD animal models, the underlying mechanisms remain poorly understood. N4-acetylcytidine (ac4C), the only known form of RNA acetylation in eukaryotes, has recently been shown to regulate mRNA stability and translation efficiency. However, the dysregulation of ac4C associated with abnormal protein expression levels in the brain of early-stage mouse models of AD remains to be elucidated. Methods This study investigated ac4C modifications, mRNA and protein expression in the hippocampus of 3 and 6-month-old 5×FAD mice, a mouse model of AD, and wild-type (WT) littermates. The multi-omics analysis was performed: acetylated RNA immunoprecipitation followed by next-generation sequencing (acRIP-seq) to identify ac4C mRNAs, deep RNA sequencing (RNA-seq) to quantify mRNA abundance, and label-free quantitative proteomics to assess protein expression levels. In addition, we used acRIP-qPCR, regular qPCR and western blots to verify the ac4C, mRNA and protein levels of some key genes that were identified by the high-throughput assays. Results Proteomic analysis revealed significant change of protein expression in the hippocampus of 3-months-old 5×FAD mice, compared with WT littermates. In contrast, RNA-seq analysis indicated that there were no substantial alterations in mRNA expression levels in the hippocampus of 3-months-old 5×FAD mice, compared to WT littermates. Strikingly, acRIP-seq revealed notable variations in ac4C modification on mRNAs, particularly those associated with synaptic structure and function, in the hippocampus of 3-months-old 5×FAD mice, compared with WT littermates. The ac4C modifications were found to be correlated with protein expression changes. Genes that are essential for synaptic function and cognition, including GRIN1, MAP2, and DNAJC6, exhibited reduced ac4C and protein levels in 3-months-old 5×FAD mice, without any corresponding changes in the mRNA levels, compared with WT littermates. Moreover, only a small part of dysregulated ac4C mRNAs identified in the 3-month-old 5×FAD mice were found in the 6-month-old 5×FAD mice. Conclusions Altogether these results identified abnormal ac4C modification of mRNAs that may contribute to the dysregulation of protein synthesis in the hippocampus from an early-stage mouse model of AD.
研究领域:
神经生物学
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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
Advanced Science
·
2025
·
IF 14.1
Yu-Juan Zhan,Chun-Miao Deng,Lin Tang,Shu-Jun Li,Tao-Yang Xu,Xian Wei,Xin-Yi Zhang,Can-Can Zheng,Li Deng,Cui Shao,Zhong-Min Ouyang,Alfred King-Yin Lam,Rong Zhang,Jun Liu,Xing-Yuan Shi,Zhen-Yu Pan,Wei Dai,Ming-Liang He,Simon Law,Xu Li,Xiao-Bing Chen,Cheng Zhou,Bin Li,Wen-Wen Xu
N-acetyltransferase 10 (NAT10)-catalyzed N4-acetylcytidine (ac4C) modification has been reported to drive tumor metastasis. Lysosomal dysregulation plays an important role in human diseases, but its function in esophageal cancer metastasis is unclear. It remains unknown whether NAT10 regulates lysosomal function, and the underlying mechanism and treatment strategy warrants investigation. Here, a novel role of NAT10 in inducing lysosomal acidification is revealed, and the clinical and biological significance of ATP6V0E1 in tumor metastasis is uncovered. Mechanistically, NAT10 promotes the translation efficiency of ATPase H + transporting V0 subunit e1 (ATP6V0E1) mRNA in an ac4C-dependent manner to facilitate ATP6V0E1 expression and vacuolar H + -ATPase (v-ATPase) activity, enhancing the lysosomal degradation of E-cadherin, ultimately accelerating tumor metastasis. Furthermore, G-749 is screened and identified as a novel NAT10 inhibitor capable of effectively impeding lysosomal acidification and tumor metastasis by disrupting the NAT10-Ubiquitin-specific Peptidase 39 (USP39) interaction. Overall, the results unveil a novel role of ac4C modifications in regulating lysosomal acidification and propose a potential strategy by targeting NAT10 to inhibit esophageal cancer metastasis.
研究领域:
癌症生物学
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分子生物学
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生物化学
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细胞生物学
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肿瘤生物学
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RNA修饰
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药理学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Endocrinology
·
2022
·
IF 6.055
Jiayu Lin,Yuting Xiang,Jiana Huang,Haitao Zeng,Yanyan Zeng,Jiawen Liu,Taibao Wu,Qiqi Liang,Xiaoyan Liang,Jingjie Li,Chuanchuan Zhou
In vitro maturation (IVM) refers to the process of developing immature oocytes into the mature in vitro under the microenvironment analogous to follicle fluid. It is an important technique for patients with polycystic ovary syndrome and, especially, those young patients with the need of fertility preservation. However, as the mechanisms of oocyte maturation have not been fully understood yet, the cultivation efficiency of IVM is not satisfactory. It was confirmed in our previous study that oocyte maturation was impaired after N-acetyltransferase 10 (NAT10) knockdown (KD). In the present study, we further explored the transcriptome alteration of NAT10-depleted oocytes and found that O-GlcNAcase ( OGA ) was an important target gene for NAT10-mediated ac4C modification in oocyte maturation. NAT10 might regulate OGA stability and expression by suppressing its degradation. To find out whether the influence of NAT10-mediated ac4C on oocyte maturation was mediated by OGA , we further explored the role of OGA in IVM. After knocking down OGA of oocytes, oocyte maturation was inhibited. In addition, as oocytes matured, OGA expression increased and, conversely, O-linked N-acetylglucosamine (O-GlcNAc) level decreased. On the basis of NAT10 KD transcriptome and OGA KD transcriptome data, NAT10-mediated ac4C modification of OGA might play a role through G protein-coupled receptors, molecular transduction, nucleosome DNA binding, and other mechanisms in oocyte maturation. Rsph6a , Gm7788 , Gm41780 , Trpc7 , Gm29036 , and Gm47144 were potential downstream genes. In conclusion, NAT10 maintained the stability of OGA transcript by ac4C modification on it, thus positively regulating IVM. Moreover, our study revealed the regulation mechanisms of oocytes maturation and provided reference for improving IVM outcomes. At the same time, the interaction between mRNA ac4C modification and protein O-GlcNAc modification was found for the first time, which enriched the regulation network of oocyte maturation.
研究领域:
生殖生物学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）