GeneSilencingByCondensin

Understanding how chromosome organization and hence chromosome organizing factors regulate gene expression has become an important challenge of modern biology. Studies performed during the past two decades identified the condensin complex as a universal chromosome organizing enzyme, conserved from bacteria to human, which condenses the genome and regulates its expression, mostly by silencing genes. Yet, how condensin drives chromosome condensation and represses gene expression remain poorly understood. Notably, the extent to which those two activities are related to each other is still unclear. Indeed, the mechanisms underlying condensin-mediated gene regulation have been poorly investigated thus far and the few available data lead to divergent conclusions. Some studies suggest that condensin complexes repress gene expression by compacting chromatin, thereby limiting access to RNA polymerases. Others imply that condensin-mediated chromosome condensation is insufficient to ensure a robust transcriptional silencing. In that context, we decided to investigate the role of condensin is gene silencing in the fission yeast Schizosaccharomyces pombe which is the model of choice for studying chromatin and gene silencing. Consistent with the idea of an evolutionarily-conserved mechanism, we found that condensin takes part in gene silencing in fission yeast as well. However, and most importantly, our results point towards an unexpected mechanism and suggest that the model of a transcriptional silencing based on chromatin condensation must be reconsidered. We collected robust preliminary data suggesting that condensin silences genes, at least in part, at the post-transcriptional level, through controlled RNA degradation. We found condensin bound to a ribonuclease and RNA-binding proteins. Moreover, those interactions seem conserved in human, suggesting that condensin regulates gene expression within a conserved network of functional and physical interactions with RNA processing factors. This opens the possibility of hitherto ignored functional links between condensin, genome architecture and controlled RNA turn-over. The objective of this research project is to further decipher the mode of action of condensin in gene silencing in both fission yeast and human cells. For that, we propose to identify and characterize critical interactions between condensin, silencing factors, chromatin regions and/or RNAs that engage condensin into gene silencing in both fission yeast and human cells. This ambitious and ground-breaking project is based on robust preliminary data and will combine innovative and interdisciplinary approaches conducted by three complementary laboratories which are already productive as a consortium. Since the organization of the genome, the condensation of chromosomes and the gene silencing operated by condensin are all ubiquitous processes, the knowledge generated by this project will be of general interest.