{"title":"人胎儿组织RNA-m5C调控图谱揭示了Nsun2/Jarid2/Alyref轴的活性","authors":"Xiujuan Hu, Chenyue Ding, Jiafeng Lu, Jincheng Li, Xiaolong Ren, Wenjuan Xia, Chunfeng Qian, Hong Li, Hoi-Hung Cheung, Boxian Huang","doi":"10.1016/j.jare.2025.08.004","DOIUrl":null,"url":null,"abstract":"<h3>Introduction</h3>Cytosine methylation (m5C) is a pivotal RNA modification essential for human fetal development, yet its tissue-specific distribution and regulatory mechanisms remain largely undefined.<h3>Objectives</h3>This study aimed to construct a tissue-specific atlas of m5C distribution across human fetal tissues and to dissect the epigenetic crosstalk between RNA methylation and epigenetic regulation. Specifically, we focused on how Nsun2-mediated m5C modifications influence chromatin dynamics and histone modification patterns during fetal development.<h3>Methods</h3>We performed RNA bisulfite sequencing (m5C-Seq) and transcriptome profiling (RNA-Seq) across seven distinct human fetal tissues. To explore the functional roles of m5C, we employed Nsun2 conditional knockout and Nsun5 knockout mouse models. We further integrated multiple experimental approaches, including dot blot assays, immunofluorescence microscopy, Co-IP, CUT&Tag and ATAC-Seq, to examine the functional connections between m5C modification, histone modifications and chromatin accessibility.<h3>Results</h3>We established the first comprehensive atlas of m5C modifications across human fetal tissues, revealing distinct tissue-specific methylation patterns. We further demonstrated that m5C-modified transcripts maintain gene expression homeostasis and regulate critical developmental transcriptional programs through alternative splicing. Mechanistically, we found that Nsun2 recruits the Jarid2/Ezh2 complex and regulates its activity via m5C-dependent recognition by Alyref. This pathway coordinates histone modifications and chromatin accessibility, supporting proper fetal development.<h3>Conclusion</h3>Our study presents a high-resolution, comprehensive tissue-specific m5C landscape during human fetal development, serving as a foundational resource for developmental epigenetics research. Subsequently, we identified a novel regulatory axis linking Nsun2, the Jarid2/Ezh2 complex, m5C modification patterns and Alyref functionality. This pathway integrates RNA methylation, histone modification and chromatin accessibility to precisely orchestrate fetal development, advancing our understanding of epigenetic regulation and offering new insights into potential therapeutic targets for developmental disorders.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"35 1","pages":""},"PeriodicalIF":13.0000,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"RNA-m5C regulatory atlas of human fetal tissues uncover the activities of Nsun2/Jarid2/Alyref axis\",\"authors\":\"Xiujuan Hu, Chenyue Ding, Jiafeng Lu, Jincheng Li, Xiaolong Ren, Wenjuan Xia, Chunfeng Qian, Hong Li, Hoi-Hung Cheung, Boxian Huang\",\"doi\":\"10.1016/j.jare.2025.08.004\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<h3>Introduction</h3>Cytosine methylation (m5C) is a pivotal RNA modification essential for human fetal development, yet its tissue-specific distribution and regulatory mechanisms remain largely undefined.<h3>Objectives</h3>This study aimed to construct a tissue-specific atlas of m5C distribution across human fetal tissues and to dissect the epigenetic crosstalk between RNA methylation and epigenetic regulation. Specifically, we focused on how Nsun2-mediated m5C modifications influence chromatin dynamics and histone modification patterns during fetal development.<h3>Methods</h3>We performed RNA bisulfite sequencing (m5C-Seq) and transcriptome profiling (RNA-Seq) across seven distinct human fetal tissues. To explore the functional roles of m5C, we employed Nsun2 conditional knockout and Nsun5 knockout mouse models. We further integrated multiple experimental approaches, including dot blot assays, immunofluorescence microscopy, Co-IP, CUT&Tag and ATAC-Seq, to examine the functional connections between m5C modification, histone modifications and chromatin accessibility.<h3>Results</h3>We established the first comprehensive atlas of m5C modifications across human fetal tissues, revealing distinct tissue-specific methylation patterns. We further demonstrated that m5C-modified transcripts maintain gene expression homeostasis and regulate critical developmental transcriptional programs through alternative splicing. Mechanistically, we found that Nsun2 recruits the Jarid2/Ezh2 complex and regulates its activity via m5C-dependent recognition by Alyref. This pathway coordinates histone modifications and chromatin accessibility, supporting proper fetal development.<h3>Conclusion</h3>Our study presents a high-resolution, comprehensive tissue-specific m5C landscape during human fetal development, serving as a foundational resource for developmental epigenetics research. Subsequently, we identified a novel regulatory axis linking Nsun2, the Jarid2/Ezh2 complex, m5C modification patterns and Alyref functionality. This pathway integrates RNA methylation, histone modification and chromatin accessibility to precisely orchestrate fetal development, advancing our understanding of epigenetic regulation and offering new insights into potential therapeutic targets for developmental disorders.\",\"PeriodicalId\":14952,\"journal\":{\"name\":\"Journal of Advanced Research\",\"volume\":\"35 1\",\"pages\":\"\"},\"PeriodicalIF\":13.0000,\"publicationDate\":\"2025-08-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Advanced Research\",\"FirstCategoryId\":\"103\",\"ListUrlMain\":\"https://doi.org/10.1016/j.jare.2025.08.004\",\"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":"Journal of Advanced Research","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1016/j.jare.2025.08.004","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}
RNA-m5C regulatory atlas of human fetal tissues uncover the activities of Nsun2/Jarid2/Alyref axis
Introduction
Cytosine methylation (m5C) is a pivotal RNA modification essential for human fetal development, yet its tissue-specific distribution and regulatory mechanisms remain largely undefined.
Objectives
This study aimed to construct a tissue-specific atlas of m5C distribution across human fetal tissues and to dissect the epigenetic crosstalk between RNA methylation and epigenetic regulation. Specifically, we focused on how Nsun2-mediated m5C modifications influence chromatin dynamics and histone modification patterns during fetal development.
Methods
We performed RNA bisulfite sequencing (m5C-Seq) and transcriptome profiling (RNA-Seq) across seven distinct human fetal tissues. To explore the functional roles of m5C, we employed Nsun2 conditional knockout and Nsun5 knockout mouse models. We further integrated multiple experimental approaches, including dot blot assays, immunofluorescence microscopy, Co-IP, CUT&Tag and ATAC-Seq, to examine the functional connections between m5C modification, histone modifications and chromatin accessibility.
Results
We established the first comprehensive atlas of m5C modifications across human fetal tissues, revealing distinct tissue-specific methylation patterns. We further demonstrated that m5C-modified transcripts maintain gene expression homeostasis and regulate critical developmental transcriptional programs through alternative splicing. Mechanistically, we found that Nsun2 recruits the Jarid2/Ezh2 complex and regulates its activity via m5C-dependent recognition by Alyref. This pathway coordinates histone modifications and chromatin accessibility, supporting proper fetal development.
Conclusion
Our study presents a high-resolution, comprehensive tissue-specific m5C landscape during human fetal development, serving as a foundational resource for developmental epigenetics research. Subsequently, we identified a novel regulatory axis linking Nsun2, the Jarid2/Ezh2 complex, m5C modification patterns and Alyref functionality. This pathway integrates RNA methylation, histone modification and chromatin accessibility to precisely orchestrate fetal development, advancing our understanding of epigenetic regulation and offering new insights into potential therapeutic targets for developmental disorders.
期刊介绍:
Journal of Advanced Research (J. Adv. Res.) is an applied/natural sciences, peer-reviewed journal that focuses on interdisciplinary research. The journal aims to contribute to applied research and knowledge worldwide through the publication of original and high-quality research articles in the fields of Medicine, Pharmaceutical Sciences, Dentistry, Physical Therapy, Veterinary Medicine, and Basic and Biological Sciences.
The following abstracting and indexing services cover the Journal of Advanced Research: PubMed/Medline, Essential Science Indicators, Web of Science, Scopus, PubMed Central, PubMed, Science Citation Index Expanded, Directory of Open Access Journals (DOAJ), and INSPEC.