nat10介导的n4 -乙酰胞苷修饰增强Nfatc1翻译,加剧绝经后骨质疏松症的破骨细胞发生

IF 9.1 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Xiaoyi Mo, Keyu Meng, Bohan Xu, Zehui Li, Shanwei Lan, Zhengda Ren, Xin Xiang, Peiqian Zou, Zesen Chen, Zhongming Lai, Xiang Ao, Zhongyuan Liu, Wanjing Shang, Bingyang Dai, Li Luo, Jiajia Xu, Zhizhang Wang, Zhongmin Zhang
{"title":"nat10介导的n4 -乙酰胞苷修饰增强Nfatc1翻译,加剧绝经后骨质疏松症的破骨细胞发生","authors":"Xiaoyi Mo, Keyu Meng, Bohan Xu, Zehui Li, Shanwei Lan, Zhengda Ren, Xin Xiang, Peiqian Zou, Zesen Chen, Zhongming Lai, Xiang Ao, Zhongyuan Liu, Wanjing Shang, Bingyang Dai, Li Luo, Jiajia Xu, Zhizhang Wang, Zhongmin Zhang","doi":"10.1073/pnas.2423991122","DOIUrl":null,"url":null,"abstract":"Increased differentiation or activity of osteoclasts is the key pathogenic factor of postmenopausal osteoporosis (PMOP). N4‐acetylcytidine (ac4C) modification, catalyzed by Nat10, is a novel posttranscriptional mRNA modification related to many diseases. However, its impact on regulating osteoclast activation in PMOP remains uncertain. Here, we initially observed that Nat10-mediated ac4C positively correlates with osteoclast differentiation of monocytes and low bone mass in PMOP. The specific knockout of Nat10 in monocytes and remodelin, a Nat10 inhibitor, alleviates ovariectomized (OVX)-induced bone loss by downregulating osteoclast differentiation. Mechanistically, epitranscriptomic analyses reveal that the nuclear factor of activated T cells cytoplasmic 1 (Nfatc1) is the key downstream target of ac4C modification during osteoclast differentiation. Subsequently, translatomic results demonstrate that Nat10-mediated ac4C enhances the translation efficiency (TE) of Nfatc1, thereby inducing Nfatc1 expression and consequent osteoclast maturation. Cumulatively, these findings reveal the promotive role of Nat10 in osteoclast differentiation and PMOP from a novel field of RNA modifications and suggest that Nat10 can be a target of epigenetic therapy for preventing bone loss in PMOP.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"85 1","pages":""},"PeriodicalIF":9.1000,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Nat10-mediated N4-acetylcytidine modification enhances Nfatc1 translation to exacerbate osteoclastogenesis in postmenopausal osteoporosis\",\"authors\":\"Xiaoyi Mo, Keyu Meng, Bohan Xu, Zehui Li, Shanwei Lan, Zhengda Ren, Xin Xiang, Peiqian Zou, Zesen Chen, Zhongming Lai, Xiang Ao, Zhongyuan Liu, Wanjing Shang, Bingyang Dai, Li Luo, Jiajia Xu, Zhizhang Wang, Zhongmin Zhang\",\"doi\":\"10.1073/pnas.2423991122\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Increased differentiation or activity of osteoclasts is the key pathogenic factor of postmenopausal osteoporosis (PMOP). N4‐acetylcytidine (ac4C) modification, catalyzed by Nat10, is a novel posttranscriptional mRNA modification related to many diseases. However, its impact on regulating osteoclast activation in PMOP remains uncertain. Here, we initially observed that Nat10-mediated ac4C positively correlates with osteoclast differentiation of monocytes and low bone mass in PMOP. The specific knockout of Nat10 in monocytes and remodelin, a Nat10 inhibitor, alleviates ovariectomized (OVX)-induced bone loss by downregulating osteoclast differentiation. Mechanistically, epitranscriptomic analyses reveal that the nuclear factor of activated T cells cytoplasmic 1 (Nfatc1) is the key downstream target of ac4C modification during osteoclast differentiation. Subsequently, translatomic results demonstrate that Nat10-mediated ac4C enhances the translation efficiency (TE) of Nfatc1, thereby inducing Nfatc1 expression and consequent osteoclast maturation. Cumulatively, these findings reveal the promotive role of Nat10 in osteoclast differentiation and PMOP from a novel field of RNA modifications and suggest that Nat10 can be a target of epigenetic therapy for preventing bone loss in PMOP.\",\"PeriodicalId\":20548,\"journal\":{\"name\":\"Proceedings of the National Academy of Sciences of the United States of America\",\"volume\":\"85 1\",\"pages\":\"\"},\"PeriodicalIF\":9.1000,\"publicationDate\":\"2025-04-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Proceedings of the National Academy of Sciences of the United States of America\",\"FirstCategoryId\":\"103\",\"ListUrlMain\":\"https://doi.org/10.1073/pnas.2423991122\",\"RegionNum\":1,\"RegionCategory\":\"综合性期刊\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MULTIDISCIPLINARY SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Proceedings of the National Academy of Sciences of the United States of America","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1073/pnas.2423991122","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
引用次数: 0

摘要

破骨细胞分化或活性增高是绝经后骨质疏松症(PMOP)的关键致病因素。N4‐乙酰胞苷(ac4C)修饰是由Nat10催化的一种新的转录后mRNA修饰,与许多疾病有关。然而,其在调节破骨细胞活化中的作用仍不确定。在这里,我们初步观察到nat10介导的ac4C与ppap中单核细胞的破骨细胞分化和低骨量呈正相关。单核细胞特异性敲除Nat10和重构蛋白(一种Nat10抑制剂)可通过下调破骨细胞分化来减轻卵巢切除(OVX)诱导的骨质流失。机制上,外转录组学分析显示活化T细胞胞质1的核因子(Nfatc1)是破骨细胞分化过程中ac4C修饰的关键下游靶点。随后,翻译结果表明,nat10介导的ac4C提高了Nfatc1的翻译效率(TE),从而诱导Nfatc1的表达和随后的破骨细胞成熟。综上所述,这些发现从RNA修饰的新领域揭示了Nat10在破骨细胞分化和PMOP中的促进作用,并表明Nat10可以成为表观遗传治疗预防PMOP骨质流失的靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Nat10-mediated N4-acetylcytidine modification enhances Nfatc1 translation to exacerbate osteoclastogenesis in postmenopausal osteoporosis
Increased differentiation or activity of osteoclasts is the key pathogenic factor of postmenopausal osteoporosis (PMOP). N4‐acetylcytidine (ac4C) modification, catalyzed by Nat10, is a novel posttranscriptional mRNA modification related to many diseases. However, its impact on regulating osteoclast activation in PMOP remains uncertain. Here, we initially observed that Nat10-mediated ac4C positively correlates with osteoclast differentiation of monocytes and low bone mass in PMOP. The specific knockout of Nat10 in monocytes and remodelin, a Nat10 inhibitor, alleviates ovariectomized (OVX)-induced bone loss by downregulating osteoclast differentiation. Mechanistically, epitranscriptomic analyses reveal that the nuclear factor of activated T cells cytoplasmic 1 (Nfatc1) is the key downstream target of ac4C modification during osteoclast differentiation. Subsequently, translatomic results demonstrate that Nat10-mediated ac4C enhances the translation efficiency (TE) of Nfatc1, thereby inducing Nfatc1 expression and consequent osteoclast maturation. Cumulatively, these findings reveal the promotive role of Nat10 in osteoclast differentiation and PMOP from a novel field of RNA modifications and suggest that Nat10 can be a target of epigenetic therapy for preventing bone loss in PMOP.
求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
CiteScore
19.00
自引率
0.90%
发文量
3575
审稿时长
2.5 months
期刊介绍: The Proceedings of the National Academy of Sciences (PNAS), a peer-reviewed journal of the National Academy of Sciences (NAS), serves as an authoritative source for high-impact, original research across the biological, physical, and social sciences. With a global scope, the journal welcomes submissions from researchers worldwide, making it an inclusive platform for advancing scientific knowledge.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信