A dynamic model of gene activation in response to hypoxia accounting for both HIF-1 and HIF-2.

We developed an ordinary differential equations (ODEs) model of hypoxia signaling that, in addition to HIF-1α, takes into account also HIF-2α. Our model can be separated into two parts, the first, describing the production and degradation of the α subunits of HIF-1 and HIF-2, and their accumulation in response to hypoxia; and the second, describing how the α subunits cooperate with the β subunit in binding to cis-regulatory regions and activation of HIF-target genes in response to hypoxia. In our previous work [1], using the first part of our model trained on time-series data from 0.9 % hypoxia, we successfully predicted the response of the system to a further drop of the oxygen to 0.3 % hypoxia. This modeling result contributed to explaining the mechanism of the switch of the control from HIF-1 to HIF-2 during the response of human primary endothelial cells to hypoxia. In another work [2], we experimentally demonstrated a linear proportionality between the counts of motifs assigned to HIF-1 in promoter open chromatin regions of genes and the effects of HIF-1 on the induction of these genes under hypoxia. We furthermore showed that such a proportionality is predicted by the subset of the ODE model of Nguyen et al. (2013) [3] common with the second part of our ODE model. In the current work, we provide the details of our full ODE model and show that it leads to a prediction that HIF-1β can be a limiting factor of the response to hypoxia.