Mid-Term Report Summary - CHROMATINRNA (The role of CpG island RNAs and Polycomb-RNA interactions in developmental gene regulation)
Polycomb repressive complex 2 (PRC2) modifies chromatin to maintain genes in a repressed state during development. PRC2 is required for embryogenesis, for embryonic stem cell (ESC) pluripotency and for the specialization of adult cell types. PRC2 is primarily associated with CpG islands at repressed genes and much research has been focused on identifying the determinants responsible for the pattern in which PRC2 is recruited to chromatin. PRC2 also possesses RNA binding activity and it is postulated the RNAs also play a role in PRC2 recruitment to chromatin. However, the RNAs that bind PRC2 in cells, the subunits that mediate these interactions, and the role of RNA in PRC2 recruitment to chromatin have all remained unclear. The aim of this ERC project is to determine the role of RNA binding for PRC2 function. By performing iCLIP for PRC2 in comparison with other RNA binding proteins, we have shown that PRC2 binds nascent RNA at essentially all active genes. Although interacting with RNA promiscuously, PRC2 binding is enriched at specific locations within RNAs, primarily exon-intron boundaries and the 3’UTR. Deletion of other PRC2 subunits reveals that the PRC2 subunit SUZ12 is sufficient to establish this RNA binding profile. Contrary to prevailing models, we have also demonstrated that the interaction of PRC2 with RNA or chromatin is mutually antagonistic in cells and in vitro. RNA degradation in cells triggers PRC2 recruitment to CpG islands at active genes. Correspondingly, release of PRC2 from chromatin in cells increases RNA binding. Consistent with this, RNA and nucleosomes compete for PRC2 binding in vitro. We propose a new model in which RNA prevents PRC2 recruitment to chromatin at active genes and that mutual antagonism between RNA and chromatin underlies the pattern of PRC2 chromatin association across the genome.
Record Number: 187761 / Last updated on: 2016-08-23