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Complex networks of miRNA-transcription factors mediate gene dosage compensation in aneuploid cancer

Acon, M. S.; Oviedo, G.; Baez, E.; Vasquez-Vargas, G.; Guevara-Coto, J.; Segura-Castillo, A.; Siles-Canales, F.; Quiros-Barrantes, S.; Mendes, P.; Mora-Rodriguez, R.

2020-02-01 systems biology
10.1101/2020.01.31.928507 bioRxiv
Show abstract

Cancer complexity is consequence of enormous genomic instability leading to aneuploidy, a hallmark of most cancers. We hypothesize that dosage compensation of critical genes could arise from systems-level properties of complex networks of microRNAs (miRNA) and transcription factors (TF) as a way for cancer cells to withstand the negative effects of aneuploidy. We studied gene dosage compensation at the transcriptional level on data of the NCI-60 cancer cell line panel with the aid of computational models to identify candidate genes with low tolerance to variation in gene expression despite high variation in copy numbers. We identified a network of TF and miRNAs validated interactions with those genes to construct a mathematical model where the property of dosage compensation emerged for MYC and STAT3. Compensation was mediated by feedback and feed-forward motifs with 4 miRNAs and was dependent on the kinetic parameters of these TF-miRNA interactions, indicating that network analysis was not enough to identify this emergent property. The inhibition of miRNAs compensating MYC suggest a therapeutic potential of targeting gene dosage compensation against aneuploid cancer.

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