Supplementary Materials from Molecular stripping, targets and decoys as modulators of oscillations in the <i>NF–κB/IκBα/DNA</i> genetic network
2016-09-21T06:05:27Z (GMT) by
Eukaryotic transcription factors in the <i>NF–κB</i> family are central components of an extensive genetic network which activates cellular responses to inflammation and to a host of other external stressors. This network consists of feedback loops that involve the inhibitor <i>IκBα</i>, numerous downstream functional targets and still more numerous binding sites that do not appear to be directly functional. Under steady stimulation the regulatory network of <i>NF–κB</i> becomes oscillatory and temporal patterns of <i>NF–κB</i> pulses appear to govern the patterns of downstream gene expression needed for immune response. Understanding how the information from external stress passes to oscillatory signals and is then ultimately relayed to gene expression is a general issue in systems biology. Recently <i>in vitro</i> kinetic experiments as well as molecular simulations suggest that active stripping of <i>NF–κB</i> by <i>IκBα</i> from its binding sites can modify the traditional systems biology view of <i>NF</i>–<i>κB</i>/<i>IκBα</i> gene circuits. In this work we revise the commonly adopted minimal model of the <i>NF–κB</i> regulatory network to account for the presence of the large number of binding sites for <i>NF–κB</i> along with dissociation from these sites which may proceed either by passive unbinding or by active molecular stripping. We identify regimes where the kinetics of target and decoy unbinding and molecular stripping enter a dynamic tug of war which may either compensate each other or amplify nuclear <i>NF–κB</i> activity, leading to distinct oscillatory patterns. Our finding that decoys and stripping play a key role in shaping the <i>NF–κB</i> oscillations suggests strategies to control <i>NF–κB</i> responses by introducing artificial decoys therapeutically.