Active Regulatory Networks Of GK Rat During Diabetic Progression

Type2diabetes mellitus is a complex systemic disease, with significant disorders of metabolism. The liver plays a key role in the development of diabetes. It is difficult to evaluate the contributions of one altered gene expression level to diabetes. However, systems biology can combine huge amount of data, mathematically model the interactions among every component with biological system. So, from the view of network biology, we have performed comprehensive active regulatory network survey in Goto-Kakizaki (GK) rat and Wistar-Kyoto (WKY) rat liver microarray data.The first work is about phenotype-difference oriented identification of molecular functions for diabetes progression in GK rat. Here, we have proposed a method for detecting molecular functions of the disease by a deductive justification from phenotype level to molecular level, and used it for testing molecular functions of disease. The functions identified by the previous studies were well covered by the functions identified by our method. The result also provided some implications for molecular mechanisms. Our phenotype-difference oriented method provides some clues to bridge directly a gap between molecular signatures and phenotype data in diabetes.The second work is about network screening of GK rat liver microarray data during diabetic progression. First, we combine the known binary relationships between the transcriptional factors and their regulated genes and the biological classification scheme to get reference regulatory networks. Then, the consistency of each regulatory network with the microarray data measured in GK rat is estimated to detect the active networks under certain comditions. The results in the case of type2diabetes in the GK rat reveals:1. More pathways are active during inter-middle stage diabetes;2. Inflammation, hypoxia, increased apoptosis, decreased proliferation, and altered metabolism are characteristics and display as early as4weeks in GK rat;3. Diabetes progression accompanies insults and compensations;4.Nuclear receptors work in concert to maintain normal glycemic robustness system. This is the first comprehensive network screening study of non-insulin dependent diabetes in the GK rat based on high throughput data of the liver. We have found several important pathways playing critical roles in the diabetes progression. Our finding s also show that network screening is able to help us understand complex diastase such as diabetes, and justify the power of network systems biology approach to elucidate the essential mechanisms which could not be solved by conventional single gene-based analysis.The third work is based on the second work, which is combined by path consistency algorithm for finding master regulators in theses active regulatory networks. First, active TF-gene pairs for three periods in GK rat were extracted from the networks by the network screening. And another set of active TF-gene pairs were selected by the network inference, in consideration of the gene expression signatures for three periods between GK and WKY rats. Then, the TF-gene pairs extracted by the two methods were further curated, from viewpoints of the emergence specificity of TF in GK rat and the regulated-gene coverage of TF in the expression signature. zuinally, in the set of TF-gene pairs we identify only5TFs, including Etv4, Fus, Nr2f1, Sp2, and Tcfap2b with54regulated genes as the candidates of MRs.