Defining transcriptional response with gene expression profile and its application

Abstract

Functional normality of signal transductions pathway should be assessed by outcome of them, that is, response. With given activation state of signal transduction pathway, there are ranges of outcome to be expected with the activation state. A signal transduction pathway is considered as malfunctioning when there are significant difference of ranges of outcomes between expected and observed. On the other hand, one cannot sure about functional normality of a signal transduction pathway simply by existence of entities in abnormal state such as abnormally expressed genes in the pathway. Therefore, I defined response in terms of transcription as functional outcome of signal transduction pathways, and applied it to identify causative genes for drug resistance, where SOCS2 and JAK2 were validated experimentally as genes responsible for sensitivity of breast cancer drug. Crosstalks and changes of crosstalks occurring in malignant situation were also identified with the concept. Transcriptional response was defined as relationship between activity of a pathway and expression levels of mRNAs of genuine target genes of transcription factors operating in the pathway. To find genuine target genes from candidate target genes defined as those having DNA sequence known to be bound by transcription factors, I used correlations of mRNA expression levels of candidate target genes according to analytical results of mathematical model of transcription regulation leaving out transcription factors. Genuine target genes were found to satisfy condition that all of correlations of possible pairs of genes have strong correlation. Resistance is a major problem of a drug because evolutionary pressure exists in cancer cells. This leads cancer cells to high rate of mutation whereby new mechanism of cancer progression appear, which results in resistance to drugs at last. I suspected that genes responsible for drug resistance would have lost or gained abnormal transcriptional regulator...