| Summary: | 碩士 === 國立清華大學 === 電機工程學系 === 92 === Gene expression programs depend on recognition of regulatory motifs by transcription factors (TFs), but how TFs regulate gene expression via recognition of cis elements is still not very clear. To study this issue, we define the cis-regulatory circuit of a gene as a system that consists of the cis elements and the interactions among their recognizing TFs and we develop a dynamic model for studying the functional architecture and dynamics of the circuit. In current approaches, a cis-regulatory circuit is constructed by a mutagenesis or motif-deletion scheme, which changes the structure of the circuit and therefore cannot give intact information for constructing the circuit. In our approach, however, one difficulty is that in each circuit, there are multiple regulatory inputs, but there is only one expression output, which is not sufficient for estimating the many parameters in our model of the circuit. We overcome this difficulty by noting that within a cluster of genes with similar functions the cis elements and the interactions of their TFs overlap among genes, so that sufficient information for constructing the cis-regulatory circuit of a gene can be obtained by simultaneously employing the expression profiles of the genes in the cluster.
A novel cross-gene identification scheme is proposed to reveal how multiple TFs coordinate to regulate gene transcription in the yeast cell cycle and to uncover hidden regulatory functions of cis-regulatory circuits. The scheme constructs the cis-regulatory circuit of each gene in a cluster of genes with overlapping binding motifs. It uses microarray data and data from genome-wide analysis of TF binding locations by chromatin immunoprecipitation. Dynamic models of the cis-regulatory circuits of the genes under study are developed according to their binding motifs and all possible interactions among their TFs. The rate parameters and regulation functions of the cis-regulatory circuits are estimated from microarray data. One advantage of this approach over that based on a mutagenesis or deletion scheme is that it is based on data obtained from the intact cis-regulatory circuits. Another advantage is that a dynamic model can quantitatively characterize the regulatory function of each of the TFs that recognize the cis elements of the gene and the interactions (cooperativities) among the TFs. Our model discerns not only the activation or repression of cis-regulatory elements by TFs but also the ability of the TFs to regulate the gene expression from a systems biology point of view. This approach may be also useful for constructing cis-regulatory circuits in more complex eukaryotes than yeast. After the cis-regulatory circuits of interest are described by explicit dynamic equations, some applications will be straightforward by the analysis and comparison of explicit values in the dynamic model. For example, the evolution of cis-regulatory circuits may be studied by comparing the values of dynamic parameters of different yeast strains.
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