关于真核生物降解及代谢过程的计算机模拟.ppt

关于真核生物mRNA降解及代谢过程的计算机模拟 曹丹 亚力桑那大学分子细胞生物学系 Dan Cao and Roy Parker Howard Hughes Medical Institute & Department of Molecular Cellular Biology University of Arizona Why want to model this process? Why want to model this process(Cont’d)? An explanatory/descriptive tool 1) correction of misconceptions 2) help interpret result correctly 3) advice suitable experiment Prediction from discrepancies between simulation result and experimental result An ideal system to start knowledge-driven simulation Plenty of data available to estimate the rates for distinct steps, including steady state distribution, half-lives, effects of various mutants… Major assumptions Transcription is a zeroth order process, all other steps are first order processes All steps are irreversible No feedback loops Determine the fitness of the model with the in vivo decay network: MFA2pG & PGK1pG They represent a unstable (MFA2) and stable (PGK1) mRNA in yeast Their degradation has been extensively characterized, with lots of data available to estimate the rates. E.g: transcriptional pulse chase gel can give information for the rates of deadenylation and decapping. Strong poly (G) structure at the 3’UTR can trap the decay intermediates, give additional information about in vivo process. E.g: rates of terminal deadenylation and 3’ to 5’ decay Comparison of modeling results with experimental observations Modeling of MFA2pG in transcriptional pulse chase Modeling of PGK1pG in transcriptional pulse chase The fact that we can reproduce the experimental results by modeling suggests that our model is quite accurate, and we have a relatively robust understanding of the in vivo process. The obtaining of a good model for both MFA2pG and PGK1pG allows us to further analyze the whole network. We have used our model to examine how transcripts respond to a variety of perturbations by performing a series of in silico experiments. E.g.: increase or decr