THE LINKAGE BETWEEN TRANSCRIPTION CONTROL AND EPIGENETIC REGULATION: THE SNAIL STORY AND BEYOND

摘要: OF DISSERTATION THE LINKAGE BETWEEN TRANSCRIPTION CONTROL AND EPIGENETIC REGULATION: SNAIL STORY BEYOND Epigenetic deregulation contributes significantly to the development of multiple human diseases, including cancer. While great effort has been made elucidate underlying mechanism, our knowledge on epigenetic regulation is still fragmentary, an important gap being how diverse events coordinate control gene transcription. In first part study, we demonstrated link between Snail-mediated transcriptional and during cancer development. Specifically, found that highly conserved SNAG domain Snail sequentially structurally mimics N-terminal tail histone H3, thereby functions as a molecular “hook”, or pseudo substrate, for recruiting lysine specific demethylase 1 (LSD1) repressor complex E-cadherin promoter. Furthermore, showed LSD1 are both required repression EMT induction, their expression correlated with each other in tumor tissues. Our findings have clinical ramifications compounds mimicking may disrupt Snail-LSD1 interaction inhibit metastasis. second designed batch based structure currently screening candidates capable competing peptide binding. addition, applied pulldown/mass spectrometry-coupled analysis identify SNAG-interacting proteins, among which many chromatin enzymes modulators. Functional characterization these proteins will help process. third interacts poly(ADP-ribose) polymerase (PARP1) through potential pADPr-binding motif subject poly(ADP-ribosyl)ation, can stabilize enhanced PTEN suppression under DNA damage condition. added another layer delicate machinery, indicated PARP inhibitors be combination conventional chemotherapies target cancers high LSD1. summary, cooperates machineries induce well survival cells. contribute better appreciation network diversification therapeutic strategies against