Abstract: |
The emergence of distinct phenotypes from isogenic cells is attributed to the intricate interplay of epigenetic marks, external signals, and gene regulators at different levels including chromatin remodelers, histone modifiers, transcription factors, regulatory RNAs, etc. In order to quantify such phenomenon, mathematical models known as Gene Regulatory Networks (GRNs) are usually proposed at the level of a small set of locally-interacting genes and factors. However, it is well-established that epigenetic regulators operate globally and compete with each other for targets genome-wide. Therefore, perturbation or knockout of the activity of one regulator can redistribute the epigenetic marks across the genome and dilute the levels of competing regulators. In this paper, we propose a mathematical model the incorporates local and global competition effects between antagonistic epigenetic regulators in addition to local transcription factors to show the counter-intuitive effects of such interactions. We apply our model to recent experimental findings on the Epithelial-Mesenchymal Transition (EMT) and show that our model can explain the puzzling results of recent knockout experiments on epithelial cells, and that it provides verifiable predictions. |