The Dynamics And Functions Of MicroRNA-regulated Gene Expression Networks.

Molecular biology experienced the transition from macroscopical to micro-cosmic in the 20 century, namely, from morphologic and phenotypic de-scription to the study of the interactions between various molecules in or-ganisms. Systems biology studies the interactions between molecules with various structures and functions from the levels of cell, tissue, organ and the whole organism, quantitatively describes and predicts biological func-tion, phenotype and behavior by computational biology. Systems biology will fulfill the study from life code to life process on the basis of genome sequence which is a integrative process, i.e., from the discrimination and study of various molecules and their interactions to the study of pathway, module and network. This process may persist for a century or even longer. So systems biology is called biology of 21 century.Abiotic complex systems generally compose of relatively simple ele-ments whose combinations give rise to complex functions and behaviors. While organisms are complex systems with a great lot elements with differ-ent structures and functions whose preferential and nonlinear interactions give rise to complex functions and behaviors. So, It is emergent to build multilevel platform to study and discriminate all the molecules and their interactions and functions in the organisms, based on which computational and mathematical methods can quantitatively describe and predict their biological function.The complexity of organism and the nonlinear properties of vast num-ber of biological processes bring forward a new challenge to computational science. Organisms may exhibit nonlinear properties such as bifurcation, delay, adaptation under the dual influences of the interactions among indi-viduals and the variations of external environment. We can gain insights into the structures and functions of organisms with nonlinear dynamical modeling and analysis. In the past, it is believed that the regulation of gene expression is a task of regulatory proteins in all organisms. However, as more and more cases of post-transcriptional regulation manifested by small non-coding RNAs are being uncovered, it is recognized that post-transcriptional regulation also plays a prominent role in the regulation of cellular processes, ranging from the embryonic development to the regulation of carcinogenesis. It is predicted by computation that more that 2/3 of the human genome are regulated by microRNA. These evidences all come to the same conclusion that the post-transcription mediated by microRNA plays a significant role.In this thesis, we mainly study the dynamics and functions of microRNAs-regulated networks with nonlinear dynamical modeling. It consists of the following three parts:(1) The dynamics and function of microRNA-mediated motifs; (2) The mechanism of microRNA'positive regulation on cell cycle; (3) The regulation of p53 network by microRNA. After the introduction of systems biology, the current research with microRNA, chemical reaction dynamics and the two networks studied in this paper, i.e., cell cycle network and p53 network, we introduce the main contents and innovation points of this paper, which can be listed as follows:(1)The dynamics and funcitons of microRNA-mediated motifs.Computational predictions showed that microRNAs are embedded in a large number of gene regulatory networks, in which certain microRNA-containing motifs are recurrent. These recurrent motifs must have some important biological function. We consider four kinds of microRNAmedi-ated motifs. These four motifs are described in rate equations and their dynamical behaviours are analysed both theoretically and numerically. We find that all the four motifs are robust to the internal and external noise and the variation of the input. The properties of motif I and II are reserved after the introduction of time delays, while motif III and IV exhibit Hopf bifur-cation when time delays satisfy certain conditions. We also proved that the occurrence of Hopf bifurcation is only related to time delay, not the external input. So Hopf bifurcation is determined by the inner attributes and has nothing to do with external changes. Moreover, the occurrence of oscilla-tion is not influenced by the internal and external noise. In conclusion, the systems'dynamic behaviours arise from inner but not external changes. All the four motifs exhibit strong robustness to external and internal stochastic perturbations, which is indispensable to biological system. So the emergence of microRNA-regulation meets the requirements of evolution.(2) The mechanism of microRNA'positive regulation on cell cycle;Now it is believed that microRNAs function through base-paring with its target genes to repress its expression. But in fact the direct target genes of microRNAs maybe not the key genes in the studied biological processes, thus it is hardly to start from the existing gene regulatory network and give an analysis of the influence on its biological functions. The problem we are facing now is to find a way out to solve the difficulty. We put forward an effective method. Firstly, we find out all the target genes of the given MicroRNA from the database. Then we built its association with the key genes of the existing gene regulatory networks based on experiment observations and data analysis. Finally, study the microRNAs'influences on biological function by analyzing the path and the key genes.In the third chapter, we apply this method to study the mechanism of microRNA'positive regulation of cell cycle. Here, the key gene is CycD, and the pathway is miR369-3-Lox-CycD. The pathways are various, so are the mechanisms of microRNA's function. Generally speaking, they can be divided into two kinds: if the pathway has odd inhibitions, the microRNA has a negative regulation on the key gene, namely, represses its expression; If the pathway has even inhibitions, the microRNA has a positive regulation on the key gene, namely, up-regulation its expression. In our work, the pathway has two inhibitions. So miR369-3 has a positive regulation on CycD. We can learn the influence of miR369-3 on cell cycle by analyzing the influence of the up-regulating of CycD on cell cycle. Different pathways and the key genes make the different microRNAs'influences on the biological function. The difference can be analyzed by the above method.(3) The regulation of p53 network by microRNA.P53 is a important tumor suppressor which regulates the expression of a vast of genes. It plays a key role in tumorigenesis. Many experiments suggest that p53 regulates the expression of many members of the miR-34 family, which in turn regulate the expression of p53's downstream genes. We study the influence on the p53 network after the introduction of microRNA. Numerical analysis and numerical simulations suggest that microRNA can change the length of the oscillation. This result indicates that microRNA can refine the expressionof p53's target genes.At last, a summary of this paper and the prospect for future study are given.