MYC dosage compensation is mediated by miRNA-transcription factor interactions in aneuploid cancer
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 multi-omics data and developed a biocomputational platform to construct a mathematical model of their interaction network with miRNAs 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 with a novel genetic tug-of-war technique by overexpressing an exogenous MYC leading to over-expression of the three microRNAs involved and down-regulation 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. HighlightsThe systems-level property of gene dosage-compensation emerges in silico in miRNA-transcription factor networks depending on the kinetic parameters of its interactions. We established a criterion to identify compensated candidate genes with low variation in expression despite high copy number variation. BioNetUCR is a novel biocomputational platform to model miRNA-transcription factor interactions We present a novel genetic tug-of-war technique to experimentally validate gene dosage compensation at the transcriptional level. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/440572v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@104a93forg.highwire.dtl.DTLVardef@1039ae9org.highwire.dtl.DTLVardef@1af41c6org.highwire.dtl.DTLVardef@1073e6a_HPS_FORMAT_FIGEXP M_FIG C_FIG