A biocomputational platform for the automated construction of large-scale mathematical models of miRNA-transcription factor networks for studies on gene dosage compensation

Abstract

Abstract-Cancer complexity and resistance is mediated by cell-to-cell heterogeneity, which is the consequence of the enormous instability of its genetic material. It is unknown how cancer cells are able to withstand the effects of these alterations, while normal cells are typically very sensitive. We hypothesize that cancer requires specific type of stability to survive the enormous chromosomal alterations. This stability may be mediated by a group of genes, whose expression is tightly regulated to maintain viability through a process called gene dosage compensation. This mechanism could be mediated by systems-level properties of complex networks of microRNAs (miRNA) and transcription factors (TF), regulating gene expression despite changes in copy number. Therefore, we designed a biocomputational platform to automatically construct large-scale mathematical models regulating the expression of several candidate genes under dosage compensation. This platform has a broader potential application to other scientific questions involving miRNA and TF networks.

A synthetic circuit for buffering gene dosage variation between individual mammalian cells

“…In natural systems, chromosomal replication and volume changes during cell growth create variation in gene copy numbers or concentration. Some gene networks must buffer this variation to remain functional and conserve their properties [17][18][19][20]62,63 . For example, through the cross-regulation of its component proteins, the yeast galactose (GAL) pathway remains similarly inducible after halving the dosage of the entire GAL network 17,19 .…”