Analysis of two mechanisms of telomere maintenance based on the theory of g-Networks and stochastic automata networks

Abstract

Abstract * Background Telomeres, which are composed of repetitive nucleotide sequences at the end of chromosomes, behave as a division clock that measures replicative senescence. Under the normal physiological condition, telomeres shorten with each cell division, and cells use the telomere lengths to sense the number of divisions. Replicative senescence has been shown to occur at approximately 50–70 cell divisions, which is termed the Hayflick’s limit. However, in cancer cells telomere lengths are stabilized, thereby allowing continual cell replication by two known mechanisms: activation of telomerase and Alternative Lengthening of Telomeres (ALT). The connections between the two mechanisms are complicated and still poorly understood. * Results In this research, we propose that two different approaches, G-Networks and Stochastic Automata Networks, which are stochastic models motivated by queueing theory, are useful to identify a set of genes that play an important role in the state of interest and to infer their previously unknown correlation by obtaining both stationary and joint transient distributions of the given system. Our analysis using G-Network detects five statistically significant genes (CEBPA, FOXM1, E2F1, c-MYC, hTERT) with either mechanism, contrasted to normal cells. A new algorithm is introduced to show how the correlation between two genes of interest varies in the transient state according not only to each mechanism but also to each cell condition. * Conclusions This study expands our existing knowledge of genes associated with mechanisms of telomere maintenance and provides a platform to understand similarities and differences between telomerase and ALT in terms of the correlation between two genes in the system. This is particularly important because telomere dynamics plays a major role in many physiological and disease processes, including hematopoiesis.