UC Irvine

Individual development is a complex process with a myriad of developmental controls at multiple levels ranging from individual cells to organs and entire individuals. The development and specification of each cell ultimately encoded in the genome. But whereas the genome is the same for all cells of the same individual, cell differentiation, specialization and response to the environment is regulated at the epigenetic level by gene regulatory networks (GRNs). Functional genomics studies have revealed that protein- DNA interactions, DNA methylation and changes in chromatin accessibility are essential to maintain cell identity and that interruption of these GRNs causes defects in cell development that can lead to disease and abnormal behaviors in individuals. Given the importance of epigenetic regulation in cells, tissues, and individuals, it would be interesting to know how these GRNs are conserved and evolve during mammalian evolution and how they can go wrong in disease. In the thesis, I present functional genomics studies and expand the understanding of epigenetic control in development from four aspects: (1) changes in DNA methylation in the same individual can be used as signature of different life experiences; (2) mutations in a repressor can cause abnormal gene expression in a small group of cells that further induce the onset of muscle wasting disease FSHD; (3) comparative dynamics of chromatin accessibility during definitive endoderm differentiation can identify conserved regulatory modules as well as species-specific enhancements; (4) The canonical form of the transcription factor NRSF is stabilized in genome through motifs conversion during mammalian evolution. These results show the versatility of epigenetic control during development and disease as well as highlight evolutionary forces shaping GRNs.