Boolean gene regulatory network model of centromere function in Saccharomyces cerevisiae

Abstract

Centromeres, a highly conserved locus of eukaryotic chromosomes, have critical function for genome stability and integrity. Because their centromeric DNA sequences are necessary and sufficient for kinetochore recruitment and DNA segregation, point centromeres of Saccharomyces cerevisiae chromosomes provide an attractive system for the study of the regulation of centromere function. Using the mathematical model of Boolean gene regulatory networks, the gene regulatory dynamics of centromere region of S. cerevisiae (budding yeast), which is actively involved in the cell-cycle, has been examined. A gene regulatory network containing the relevant centromere genes of the model organism from biological databases was established and all possible cellular phenotypes subjected to a synchronous gene regulation and attracted to several basins. Gene expression in the largest attractor was compared with the biological data by obtaining changes in the cell-cycle. We show that the model for centromere function recovers a single cyclic attractor. The trajectory flow diagram plotted over all initial conditions of the system also shows good correspondence with the cell-cycle phases. Although other upstream signals are possibly involved in the regulation of centromere genes, proposed interactions with selected cell-cycle genes were sufficient to recover whole cell-cycle process. To truly clarify these proposed regulatory interactions of candidate genes for centromere function, profiling and analyzing their expression levels over time with expanded nodes/edges are required. Moreover, a previously modeled gene knock-down mechanism applied to the network and robustness versus knock-down was interpreted based on the obtained consequences.