Final Report Summary - RNAIGENREG (RNAi-mediated genome regulation)
Besides employing cutting edge microscopy techniques, we have been using a special chromatin profiling technique referred to as DamID, which led to the identification of novel physiological targets of RNAi. We discovered a class of genes that are bound by the stress response transcription factor Atf1 and which we refer to as BANCs. We found that BANC genes are associated with nuclear pore complexes (NPCs) and RNAi proteins, which are all required for their tight repression. Because RNA polymerase II occupancy is not affected in RNAi mutants at the majority of BANCs, we conclude that RNAi functions on a truly co-transcriptional level to tightly repress this class of genes under non-stressful conditions.
Finally, through a forward genetic screen we uncovered fission yeast mutants that are highly susceptible to de novo formation of heterochromatin and stable gene silencing by siRNAs. Beyond basic research, these findings are highly relevant for biotechnology and biomedicine. Specifically, inducing stable epigenetic-mediated repression of a disease-causing gene by transient delivery of siRNAs would constitute a big step forward in developing successful RNAi-based therapeutics. In the course of a follow-up project that is funded by an ERC Consolidator Grant, we will dissect the details of this repressive mechanism and test whether similar activities exist in mammalian cells.