文章基本信息

标题：MYC dosage compensation is mediated by miRNA-transcription factor interactions in aneuploid cancer
本地全文：下载
作者：ManSai Acón ; Carsten Geiß ; Jorge Torres-Calvo 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：12
页码：1-37
DOI：10.1016/j.isci.2021.103407
语种：English
出版社：Elsevier
摘要：SummaryWe hypothesize that dosage compensation of critical genes arises from systems-level properties for cancer cells to withstand the negative effects of aneuploidy. We identified several candidate genes in cancer multiomics data and developed a biocomputational platform to construct a mathematical model of their interaction network with micro-RNAs and transcription factors, where the property of dosage compensation emerged forMYCand was dependent on the kinetic parameters of its feedback interactions with three micro-RNAs. These circuits were experimentally validated using a genetic tug-of-war technique to overexpress an exogenousMYC, leading to overexpression of the three microRNAs involved and downregulation of endogenousMYC.In addition,MYCoverexpression or inhibition of its compensating miRNAs led to dosage-dependent cytotoxicity inMYC-amplified colon cancer cells. Finally, we identified negative correlation ofMYCdosage compensation with patient survival in TCGA breast cancer patients, highlighting the potential of this mechanism to prevent aneuploid cancer progression.Graphical abstractDisplay OmittedHighlights•BioNetUCR is a platform to model large miRNA-transcription factor networks•Compensated genes have low variation in expression despite high copy number variation•Gene dosage compensation depends on circuit kinetic parameters to emergein silico•A genetic tug-of-war technique validates transcriptional gene dosage compensationBioinformatics; Mathematical biosciences; Systems biology