versatility of cooperative transcriptional activation a thermodynamical modeling analysis for greater-than-additive and less-than-additive effects多功能性合作转录激活greater-than-additive热力学建模分析和less-than-additive效果.pdfVIP

Versatility of Cooperative Transcriptional Activation: A Thermodynamical Modeling Analysis for Greater-Than- Additive and Less-Than-Additive Effects 1,2 ´ 1 1 Till D. Frank *, Aimee M. Carmody , Boris N. Kholodenko 1 Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland, 2 University College Dublin School of Physics, University College Dublin, Belfield, Dublin, Ireland Abstract We derive a statistical model of transcriptional activation using equilibrium thermodynamics of chemical reactions. We examine to what extent this statistical model predicts synergy effects of cooperative activation of gene expression. We determine parameter domains in which greater-than-additive and less-than-additive effects are predicted for cooperative regulation by two activators. We show that the statistical approach can be used to identify different causes of synergistic greater-than-additive effects: nonlinearities of the thermostatistical transcriptional machinery and three-body interactions between RNA polymerase and two activators. In particular, our model-based analysis suggests that at low transcription factor concentrations cooperative activation cannot yield synergistic greater-than-additive effects, i.e., DNA transcription can only exhibit less-than-additive effects. Accordingly, transcriptional activity turns from synergistic greater-than-additive responses at relatively high transcription factor concentrations into less-than-additive responses at relatively low concentrations. In addition, two types of re-entrant phenomena are predicted. First, our analysis predicts that under particular circumstances transcriptional activity will feature a sequence of less-than-add