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bioRxiv · 10.1101/2020.01.31.928507

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.
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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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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. Complex networks of miRNA-transcription factors mediate gene dosage compensation in aneuploid cancer. https://doi.org/10.1101/2020.01.31.928507

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