APC mutations dysregulate alternative polyadenylation in cancer

IF 10.1 1区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Genome Biology Pub Date : 2024-10-07 DOI:10.1186/s13059-024-03406-4
Austin M. Gabel, Andrea E. Belleville, James D. Thomas, Jose Mario Bello Pineda, Robert K. Bradley
{"title":"APC mutations dysregulate alternative polyadenylation in cancer","authors":"Austin M. Gabel, Andrea E. Belleville, James D. Thomas, Jose Mario Bello Pineda, Robert K. Bradley","doi":"10.1186/s13059-024-03406-4","DOIUrl":null,"url":null,"abstract":"Alternative polyadenylation (APA) affects most human genes and is recurrently dysregulated in all studied cancers. However, the mechanistic origins of this dysregulation are incompletely understood. We describe an unbiased analysis of molecular regulators of poly(A) site selection across The Cancer Genome Atlas and identify that colorectal adenocarcinoma is an outlier relative to all other cancer subtypes. This distinction arises from the frequent presence of loss-of-function APC mutations in colorectal adenocarcinoma, which are strongly associated with long 3′ UTR expression relative to tumors lacking APC mutations. APC knockout similarly dysregulates APA in human colon organoids. By mining previously published APC eCLIP data, we show that APC preferentially binds G- and C-rich motifs just upstream of proximal poly(A) sites. Lastly, we find that reduced APC expression is associated with APA dysregulation in tumor types lacking recurrent APC mutations. As APC has been previously identified as an RNA-binding protein that preferentially binds 3′ UTRs during mouse neurogenesis, our results suggest that APC promotes proximal poly(A) site use and that APC loss and altered expression contribute to pervasive APA dysregulation in cancers.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"54 1","pages":""},"PeriodicalIF":10.1000,"publicationDate":"2024-10-07","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/s13059-024-03406-4","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

Alternative polyadenylation (APA) affects most human genes and is recurrently dysregulated in all studied cancers. However, the mechanistic origins of this dysregulation are incompletely understood. We describe an unbiased analysis of molecular regulators of poly(A) site selection across The Cancer Genome Atlas and identify that colorectal adenocarcinoma is an outlier relative to all other cancer subtypes. This distinction arises from the frequent presence of loss-of-function APC mutations in colorectal adenocarcinoma, which are strongly associated with long 3′ UTR expression relative to tumors lacking APC mutations. APC knockout similarly dysregulates APA in human colon organoids. By mining previously published APC eCLIP data, we show that APC preferentially binds G- and C-rich motifs just upstream of proximal poly(A) sites. Lastly, we find that reduced APC expression is associated with APA dysregulation in tumor types lacking recurrent APC mutations. As APC has been previously identified as an RNA-binding protein that preferentially binds 3′ UTRs during mouse neurogenesis, our results suggest that APC promotes proximal poly(A) site use and that APC loss and altered expression contribute to pervasive APA dysregulation in cancers.
查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
APC 突变会导致癌症中的替代多腺苷酸化失调
交替多腺苷酸化(APA)影响着大多数人类基因,并在所有研究的癌症中反复出现失调。然而,人们对这种失调的机理还不完全清楚。我们描述了对整个《癌症基因组图谱》中多聚(A)位点选择的分子调控因子的无偏见分析,并发现结直肠腺癌相对于所有其他癌症亚型是一个异常值。这种区别是由于结直肠腺癌中经常出现功能缺失的 APC 突变,与缺乏 APC 突变的肿瘤相比,这种突变与长 3′ UTR 表达密切相关。APC 基因敲除同样会导致人类结肠器官组织中的 APA 失调。通过挖掘以前发表的 APC eCLIP 数据,我们发现 APC 会优先结合近端 poly(A) 位点上游的富含 G 和 C 的基序。最后,我们发现在缺乏复发性 APC 突变的肿瘤类型中,APC 表达的减少与 APA 失调有关。我们的研究结果表明,APC 促进了近端 poly(A) 位点的使用,APC 的缺失和表达改变导致了癌症中普遍存在的 APA 失调。
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 去求助
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.
期刊最新文献
Hierarchical annotation of eQTLs by H-eQTL enables identification of genes with cell type-divergent regulation Publisher Correction: Tagging large CNV blocks in wheat boosts digitalization of germplasm resources by ultra-low-coverage sequencing The genomic portrait of the Picene culture provides new insights into the Italic Iron Age and the legacy of the Roman Empire in Central Italy scStateDynamics: deciphering the drug-responsive tumor cell state dynamics by modeling single-cell level expression changes Considerations in the search for epistasis
×
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
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 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 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1