MYC dosage compensation is mediated by miRNA-transcription factor interactions in aneuploid cancer
Summary: 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 mathemati...
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2021
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oai:doaj.org-article:a65d6bd5d804487198de0595ac10da3c2021-11-24T04:33:02ZMYC dosage compensation is mediated by miRNA-transcription factor interactions in aneuploid cancer2589-004210.1016/j.isci.2021.103407https://doaj.org/article/a65d6bd5d804487198de0595ac10da3c2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S258900422101378Xhttps://doaj.org/toc/2589-0042Summary: 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.ManSai AcónCarsten GeißJorge Torres-CalvoDiana Bravo-EstupiñanGuillermo OviedoJorge L. Arias-AriasLuis A. Rojas-MateyBaez EdwinGloriana Vásquez-VargasYendry Oses-VargasJosé Guevara-CotoAndrés Segura-CastilloFrancisco Siles-CanalesSteve Quirós-BarrantesAnne Régnier-VigourouxPedro MendesRodrigo Mora-RodríguezElsevierarticleBioinformaticsMathematical biosciencesSystems biologyScienceQENiScience, Vol 24, Iss 12, Pp 103407- (2021) |
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Bioinformatics Mathematical biosciences Systems biology Science Q ManSai Acón Carsten Geiß Jorge Torres-Calvo Diana Bravo-Estupiñan Guillermo Oviedo Jorge L. Arias-Arias Luis A. Rojas-Matey Baez Edwin Gloriana Vásquez-Vargas Yendry Oses-Vargas José Guevara-Coto Andrés Segura-Castillo Francisco Siles-Canales Steve Quirós-Barrantes Anne Régnier-Vigouroux Pedro Mendes Rodrigo Mora-Rodríguez MYC dosage compensation is mediated by miRNA-transcription factor interactions in aneuploid cancer |
| description |
Summary: 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. |
| format |
article |
| author |
ManSai Acón Carsten Geiß Jorge Torres-Calvo Diana Bravo-Estupiñan Guillermo Oviedo Jorge L. Arias-Arias Luis A. Rojas-Matey Baez Edwin Gloriana Vásquez-Vargas Yendry Oses-Vargas José Guevara-Coto Andrés Segura-Castillo Francisco Siles-Canales Steve Quirós-Barrantes Anne Régnier-Vigouroux Pedro Mendes Rodrigo Mora-Rodríguez |
| author_facet |
ManSai Acón Carsten Geiß Jorge Torres-Calvo Diana Bravo-Estupiñan Guillermo Oviedo Jorge L. Arias-Arias Luis A. Rojas-Matey Baez Edwin Gloriana Vásquez-Vargas Yendry Oses-Vargas José Guevara-Coto Andrés Segura-Castillo Francisco Siles-Canales Steve Quirós-Barrantes Anne Régnier-Vigouroux Pedro Mendes Rodrigo Mora-Rodríguez |
| author_sort |
ManSai Acón |
| title |
MYC dosage compensation is mediated by miRNA-transcription factor interactions in aneuploid cancer |
| title_short |
MYC dosage compensation is mediated by miRNA-transcription factor interactions in aneuploid cancer |
| title_full |
MYC dosage compensation is mediated by miRNA-transcription factor interactions in aneuploid cancer |
| title_fullStr |
MYC dosage compensation is mediated by miRNA-transcription factor interactions in aneuploid cancer |
| title_full_unstemmed |
MYC dosage compensation is mediated by miRNA-transcription factor interactions in aneuploid cancer |
| title_sort |
myc dosage compensation is mediated by mirna-transcription factor interactions in aneuploid cancer |
| publisher |
Elsevier |
| publishDate |
2021 |
| url |
https://doaj.org/article/a65d6bd5d804487198de0595ac10da3c |
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