The balance of power between retention and export of lncRNAs

For many years it has been known that the human genome carries the information to make proteins via an intermediate called messenger RNA.
Recent analysis of the human genome has revealed that large parts of it are copied to make other types of RNA molecules and these RNA molecules play many important functions such as regulating the activity of the chromosomes in our body as well as much more diverse functions such as regulating when plants flower. Crucially, some of these newly discovered RNA molecules which do not encode proteins are kept in the same cellular compartment as our genome i.e the nucleus, whereas the mRNAs which make proteins are transported to the cytoplasm. How the cell decides which RNAs to move to the cytoplasm and which to keep in the nucleus is currently not clear. In this project we will establish how the sorting mechanism works which decides whether RNAs should stay in the nucleus or move to the cytoplasm.

Eukaryotic cells have to retain many RNA molecules including long non-coding RNAs (lncRNAs) in the nucleus where they perform diverse functions ranging from X chromosome inactivation in mammals through to flowering control in plants. How the cell decides which RNAs to retain in the nucleus and which to export is unclear despite the central importance of this decision for eukaryotic biology. Surprisingly we have found that nuclear retained lncRNAs are decorated with the TREX mRNA export complex as well as the mRNA export receptor Nxf1, suggesting these export factors are specifically repressed on lncRNAs. In this project we will investigate the molecular mechanisms which lead to suppression of the mRNA export complex on lncRNAs thus governing nuclear retention of certain lncRNA molecules, a process of central importance to many aspects of eukaryotic biology.

The work addresses the basic biology of how the cell restricts certain types of RNA to the nucleus, such as some long non-coding RNAs and pre-mRNAs. There are three main groups of beneficiary from this work 1) Clinicians, patients suffering from motor neuron disease and the pharmaceutical industry. The most common form of familial motor neuron disease (MND) involves the nuclear export of a pre-mRNA containing a repeat expansion within an intron of the C9ORf72 gene. The export of this RNA to the cytoplasm, where it is translated to make toxic peptides is an important problem in this disease. Pre-mRNAs are normally retained in the nucleus and our studies on the mechanisms of retention of nuclear RNA species in this project will increase our understanding of this process and potentially identify suitable targets for therapeutic intervention in C9ORF72 related MND. In turn, this may lead to the development of a new class of drugs for treatment of MND which would benefit patients suffering this disease, the pharmaceutical industry and provide a greater range of treatment options for clinicians. 2) Researchers engaged on the project. The project will provide new training opportunities for the people engaged on this project and this in turn will develop their careers and contribute to the generation of a highly skilled workforce which is essential for the continued success of the U.K. economy. 3) The general public/schoolchildren. Media training will be utilised during the project to enhance the ability of the investigator to deliver an accessible educational message to the general public about the various research projects being undertaken in his laboratory and those of colleagues working in related areas in the University. This will help enhance the public understanding of science which is increasingly important, particularly with imminent large scale sequencing of human genomes through the 100,000 genome project. A series of courses will be run for schoolchildren to experience molecular biology techniques and they will be given a specific talk describing the recent research of SW, including work in this project and how this is contributing to our understanding of human cells and how they work. This will be important for inspiring schoolchildren to become the next generation of scientists in the future.