Stochastic Regulation of the Interleukin-4 Gene

This book focuses on the expression variability of highly regulated genes in multi-cellular organisms through a multidisciplinary approach combining quantitative measurements and mathematical modeling. For this purpose, the cytokine gene Interleukin-4 (IL-4) in murine type-2 (Th2) lymphocytes was chosen as prototypical model system of an inducible gene regulated at the epigenetic and transductional level. As many cytokines, IL-4 is expressed in a probabilistic manner, but the underlying molecular mechanisms behind this phenomenon are still unresolved. Through an iterative process of quantitative measurements and mathematical analysis, the author develops a computational model able to predict several system properties. The model indicates that the heterogeneity in IL-4 expression results from a rate-limiting chromatin opening during antigenic stimulation. The rate of inactivation of the promoter is slow (on the order of a cell cycle), which increases the probability of subsequent IL-4 stimulation in the same cells. As a consequence, a previously unknown short-term memory for IL-4 induction is tested and verified experimentally. The multidisciplinary approach presented here will be hopefully useful for investigating other genes highly regulated at the epigenetic level and shows the potential of system biology in revealing new properties of complex processes.