Understanding how RNA is tethered to chromatin

This project addresses where RNA is localised in the cell. Location is very important as any estate agent will tell you. The mammalian cell produces a wide range of RNA molecules with diverse functions. Some well known RNAs, such as messenger RNA, are produced in the nucleus and then exported to the cytoplasm where they encode for proteins. Many other types of RNA largely reside in the nucleus and some of them are tethered to the DNA where they regulate the production of RNA and play a role in the overall structural organisation of the nucleus. We have discovered that the HNRNPU protein plays a widespread role in tethering RNAs to DNA in the nucleus and additionally is probably involved in tethering different RNAs to each other. In this project we will characterise the nuclear RNA:DNA and RNA:RNA tethering mechanisms controlled by HNRNPU and determine the impact these processes have on mammalian gene expression.

We have shown that HNRNPU is involved in tethering a wide range of non-coding and coding RNAs to chromatin in the nucleus. This activity has wide ranging effects on gene expression including the regulation of transcription, RNA processing and RNA localisation. Recent work has also implicated the U1 snRNP in chromatin tethering of RNAs. In this project we aim to integrate these new findings to generate a unified picture for RNA:chromatin tethering mechanisms, which has broad implications not only for mammalian gene expression but also chromatin structure and nuclear organisation. We will also characterise the disrupted pattern of transcription by RNA polymerase II following HNRNPU depletion which shapes the balance between production of short and long mRNAs in the cell. The notion that non-coding and coding RNAs may be tethered to each other and to chromatin via a transcription dependent process is a relatively new concept and the players in this fascinating new area of biology are poorly understood. We believe HNRNPU plays a central role in these processes and we aim to prove this in this project.