Cells in a multicellular organism share the same set of genome and can assume multiple phenotypes. Uncovering mechanisms of regulating cell phenotype changes has become an important and active research area. This dissertation presents a collection of my combined computational and experimental efforts on studying cell phenotype transitions.
Chapter I gives a literature overview on cell phenotype conversion and regulation. One can identify four generic modules that function coordinately to regulate cell phenotypes. The whole system forms a highly interconnected network and involves a large number of molecular species for epigenetic, transcriptional and translational regulations.
Chapter II addresses how a cell interprets temporal and strength information of signals and makes cell fate decision. I performed an integrated quantitative and computational analysis on how extracellular TGF-β signal is transmitted intracellularly to activate SNAIL1 expression. I demonstrated how quantitative information of TGF-β is distributed through upstream divergent pathways then crosstalk at various places and converge on to SNAIL1. This crosstalk network interprets the duration of TGF-β signal and is robust against stochastic fluctuations.
Chapter III and IV focus on co-regulation of multiple genes that orchestrate cell functions and phenotype changes. In eukaryotic cells, the expression level of a gene is determined by both transcription factors and the local environment, such as histone modifications and three-dimensional chromosome structure. I used EMT in human cell line and neural cell differentiation process in mouse as model systems, respectively. Through performing combined analysis of data of gene expression, epigenetic modification and chromosome conformation, I examined how the local environment and transcriptional factor regulation is coupled. I discovered that genes co-regulated by a common transcription factor (TF) has tendency to be close both sequentially and spatially. The local spatial organization bridged by TFs is cell type specific. Reorganization of DNA local conformation has impact on gene co-regulation during cell phenotype transition.
The final chapter gives a brief summary of the conclusion from my computational and experimental researches in this dissertation. In this chapter, I also introduced the future work in investigating the relationship between chromosome conformation and gene regulation during cell type transition
