MYC dosage compensation is mediated by miRNA-transcription factor interactions in aneuploid cancer

• Published in: iScience Vol. 24; no. 12; p. 103407
• Main Authors: Acón, ManSai, Geiß, Carsten, Torres-Calvo, Jorge, Bravo-Estupiñan, Diana, Oviedo, Guillermo, Arias-Arias, Jorge L., Rojas-Matey, Luis A., Edwin, Baez, Vásquez-Vargas, Gloriana, Oses-Vargas, Yendry, Guevara-Coto, José, Segura-Castillo, Andrés, Siles-Canales, Francisco, Quirós-Barrantes, Steve, Régnier-Vigouroux, Anne, Mendes, Pedro, Mora-Rodríguez, Rodrigo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.12.2021; Elsevier
• Subjects: Bioinformatics; Mathematical biosciences; Systems biology; Mathematical biosciences; Systems biology; Bioinformatics
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2021.103407

We 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 for MYC and 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 exogenous MYC, leading to overexpression of the three microRNAs involved and downregulation of endogenous MYC. In addition, MYC overexpression or inhibition of its compensating miRNAs led to dosage-dependent cytotoxicity in MYC-amplified colon cancer cells. Finally, we identified negative correlation of MYC dosage compensation with patient survival in TCGA breast cancer patients, highlighting the potential of this mechanism to prevent aneuploid cancer progression. [Display omitted] •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 emerge in silico•A genetic tug-of-war technique validates transcriptional gene dosage compensation Bioinformatics; Mathematical biosciences; Systems biology