Mechanisms of epigenetic inactivation of tumor suppressor genes
During the process of tumorigenesis, oncogenes can become activated or tumor suppressor genes (TSGs) can become inactivated so that they are no longer are available to regulate cell cycle progression, apoptosis and cell migration. TSGs can become inactivated by at least three events, including mutation, deletion and epigenetic silencing. Epigenetic inactivation can involve chromatin alteration through histone modifications, the binding of repressive proteins and aberrant methylation of CpG islands, which regulate TSG expression. The molecular mechanisms responsible for maintaining the silenced state are quite well understood, however the events, which cause epigenetic deregulation of TSGs during ageing present still a major research challenge.
In this project, we aim to reveal specific factors that are involved in initiating and maintaining stable gene silencing and to understand mechanisms that protect promoters against this inactivation process. Therefore, we will investigate the order of events for gene silencing in cancer with respect to altered transcription factor binding, chromatin modifications and DNA methylation at specific tumor suppressor genes (e.g. Ras Association Domain Family 1A). Which epigenetic alteration comes first, and what are the key protein complexes that target the processes that determine the events? Moreover, we will investigate the molecular boundaries that protect transcriptionally active CpG island promoters from the spreading of transcriptionally repressive chromatin domains. Modifications of transcriptions factors by SUMOylation, insulator proteins (e.g. CTCF) and chromatin-remodeling proteins are candidates that may have key roles in the regulation of molecular boundaries and repressive chromatin structure at the promoters of tumor associated genes