Modelling epigenetic feedback in gene regulatory network consisting of three mutually inhibiting transcription factors

Regulatory biochemical networks demonstrate different levels of control - transcriptional, translational, protein activity and epigenetic. Toggle triad is a network motif consisting of three mutually repressing transcription factors each driving a distinct cell fate. We have previously demonstrated underlying multistability in a toggle triad: it can give rise to six states in total, three of which are 'single positive' (A high, B low, C low; A low, B high, C low; and A low, B low, C high) and three 'double positive' (A high, B high, C low; A high, B low, C high; and A low, B high, C high), which can be mapped on to Th1, Th2, Th17 and hybrid Th1/Th2, Th1/Th17 and Th2/Th17 states in CD4+ T cell differentiation. Here, we incorporated epigenetic feedback mechanism into the previously developed gene regulatory model for a toggle triad to study the stability of the various phenotypes of the motif identified previously and investigate the dynamics of irreversibility of cell-fate decisions as a function of epigenetic feedback incorporated on different links in the network. Our results offer insights into cell-fate decision-making vs. cell-fate commitment for a multistable network and helps understand plasticity and stability of different T-helper states.