Mammalian conservation of endogenous G-quadruplex reveals their associations with complex traits

IF 10.1 1区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Ze-Hao Zhang, Zi-Yan Wang, Cong-Hui Li, Sheng Hu Qian, Wen Zhang, Zhen-Xia Chen
{"title":"Mammalian conservation of endogenous G-quadruplex reveals their associations with complex traits","authors":"Ze-Hao Zhang, Zi-Yan Wang, Cong-Hui Li, Sheng Hu Qian, Wen Zhang, Zhen-Xia Chen","doi":"10.1186/s13059-025-03750-z","DOIUrl":null,"url":null,"abstract":"DNA G-quadruplexes (G4s) are four-stranded DNA structures. Endogenous G-quadruplexes (eG4s) have been identified as pivotal regulatory elements for gene expression in the human genome. The measurement of evolutionary conservation can be employed to ascertain the functional relevance of putative regulatory elements. However, the evolutionary profiles of human eG4s remain largely unknown. Here, we construct mammalian evolutionary profiles of human eG4s based on a comprehensive reference annotation of human eG4s from the integration of the eG4 database EndoQuad covering 41 human cell lines and our home-made G4 CUT&Tag data covering seven cell lines. We find that transposable elements contribute substantially to the evolutionary spread of primate-specific eG4s. A total of 92,910 highly conserved human eG4s were identified under mammalian constraint. By developing and utilizing the eG4 prediction tool eG4finder, which is based on a large language model, we verify the high structural conservation of highly conserved eG4s. The enrichment of highly conserved eG4s in developmental and aging pathways highlights their potential significance in key biological processes. Notably, highly conserved eG4s exhibit higher regulatory potential, regulatory activity and affinity for transcription factors. We demonstrate that highly conserved eG4s are the most powerful transcriptional activation elements in the total eG4 collection. Meanwhile, trait-associated variants and variants affecting the expression of high phenotypic severity genes are most enriched in highly conserved eG4s. Our study highlights the important regulatory functions and close association with complex human traits of human eG4s that are highly conserved in the mammalian lineage.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"30 1","pages":""},"PeriodicalIF":10.1000,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Genome Biology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1186/s13059-025-03750-z","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

DNA G-quadruplexes (G4s) are four-stranded DNA structures. Endogenous G-quadruplexes (eG4s) have been identified as pivotal regulatory elements for gene expression in the human genome. The measurement of evolutionary conservation can be employed to ascertain the functional relevance of putative regulatory elements. However, the evolutionary profiles of human eG4s remain largely unknown. Here, we construct mammalian evolutionary profiles of human eG4s based on a comprehensive reference annotation of human eG4s from the integration of the eG4 database EndoQuad covering 41 human cell lines and our home-made G4 CUT&Tag data covering seven cell lines. We find that transposable elements contribute substantially to the evolutionary spread of primate-specific eG4s. A total of 92,910 highly conserved human eG4s were identified under mammalian constraint. By developing and utilizing the eG4 prediction tool eG4finder, which is based on a large language model, we verify the high structural conservation of highly conserved eG4s. The enrichment of highly conserved eG4s in developmental and aging pathways highlights their potential significance in key biological processes. Notably, highly conserved eG4s exhibit higher regulatory potential, regulatory activity and affinity for transcription factors. We demonstrate that highly conserved eG4s are the most powerful transcriptional activation elements in the total eG4 collection. Meanwhile, trait-associated variants and variants affecting the expression of high phenotypic severity genes are most enriched in highly conserved eG4s. Our study highlights the important regulatory functions and close association with complex human traits of human eG4s that are highly conserved in the mammalian lineage.
哺乳动物内源性g -四重体的保护揭示了它们与复杂性状的关联
DNA g -四联体(G4s)是一种四链DNA结构。内源性g -四重复合物(eG4s)已被确定为人类基因组基因表达的关键调控元件。进化守恒的测量可以用来确定假定的调控元件的功能相关性。然而,人类eG4s的进化特征在很大程度上仍然未知。在此,我们整合了包含41个人类细胞系的eG4数据库EndoQuad和我们自制的包含7个细胞系的G4 CUT&Tag数据,基于对人类eG4的综合参考注释,构建了人类eG4的哺乳动物进化图谱。我们发现转座因子对灵长类特异性eG4s的进化传播有重要贡献。在哺乳动物约束下,共鉴定出92910个高度保守的人类eg4。通过开发和利用基于大型语言模型的eG4预测工具eG4finder,我们验证了高度保守的eG4具有高度的结构保守性。在发育和衰老途径中富集高度保守的eg4,凸显了它们在关键生物学过程中的潜在意义。值得注意的是,高度保守的eG4s表现出更高的调控潜力、调控活性和对转录因子的亲和力。我们证明高度保守的eG4是所有eG4集合中最强大的转录激活元件。同时,性状相关变异和影响高表型严重度基因表达的变异在高度保守的eg4中最为富集。我们的研究强调了在哺乳动物谱系中高度保守的人类eG4s的重要调控功能和与复杂人类特征的密切联系。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Genome Biology
Genome Biology Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
21.00
自引率
3.30%
发文量
241
审稿时长
2 months
期刊介绍: Genome Biology stands as a premier platform for exceptional research across all domains of biology and biomedicine, explored through a genomic and post-genomic lens. With an impressive impact factor of 12.3 (2022),* the journal secures its position as the 3rd-ranked research journal in the Genetics and Heredity category and the 2nd-ranked research journal in the Biotechnology and Applied Microbiology category by Thomson Reuters. Notably, Genome Biology holds the distinction of being the highest-ranked open-access journal in this category. Our dedicated team of highly trained in-house Editors collaborates closely with our esteemed Editorial Board of international experts, ensuring the journal remains on the forefront of scientific advances and community standards. Regular engagement with researchers at conferences and institute visits underscores our commitment to staying abreast of the latest developments in the field.
×
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