RNA processing and eukaryotic gene expression regulation

Lead Research Organisation: MRC Human Genetics Unit

Abstract

DNA carries the genetic information of a cell and consists of thousands of genes that encode all the information required to make proteins. Genes (DNA) are copied into a molecule called RNA (pre-mRNA) in a process known as transcription. This pre-mRNA is then processed so that non-coding parts are removed and is then transported out of the nucleus to be ultimately translated into proteins in the cytoplasm. Our laboratory is interested in different aspects of how the pre-mRNA is accurately processed into mature mRNA, which then undergoes translation as part of the protein synthesis to produce proteins. Defects in RNA processing are linked to human disease. Our research program is at the basic end of the spectrum and we expect to contribute to the general knowledge in the areas of RNA processing and nuclear structure that could be applicable to human genetics.

Technical Summary

Gene expression is extensively regulated at the post-transcriptional level. The fundamental steps of eukaryotic RNA processing have been characterised in great detail, but knowledge of how the disruption of these processes contributes to human disease has only recently begun to emerge. The major aim of this programme is to study the mechanisms for the post-transcriptional regulation of gene expression. Our laboratory studies different aspects of RNA processing, including alternative splicing regulation, microRNA processing and nonsense-mediated decay.||The predominance of alternative splicing has become evident when completion of the human genome sequence revealed that a large proteomic complexity is achieved with a limited number of genes. We are particularly interested in the trans-acting factors that are involved in the regulation of alternative splicing, such as the SR proteins and hnRNP A/B type of proteins. These proteins have antagonistic activities and their molar ratio influence different modes of alternative splicing in vivo and may represent a mechanism for tissue-specific or developmental regulation of gene expression.||We also study the subcellular distribution of RNA processing factors and how this could be affected by extracellular signals.||The relevance of RNA processing, in particular pre-mRNA splicing, to human disease has emerged recently. Disturbances in pre-mRNA splicing have been found in a variety of disease processes. Splice site mutations are exemplified by some forms of thalassemia. However, in many cases, such as the dysregulated splicing of CD44 found in many human malignancies, mutations are not found in the target gene and it is presumed that the changes are due to changes in the milieu of splicing factors in the diseased cell. Therefore, cis-acting sequences and trans-acting factors that lead to aberrant RNA processing associated with human disease will be an important target of molecular therapies. ||Interestingly, pre-mRNA splicing is not only important to form the mature mRNA, that is exported to the cytoplasm, but also influences processing events that act downstream of it. Therefore, we have expanded our interest to RNA processing events that act downstream of pre-mRNA splicing, including nonsense-mediated decay and translational regulation.||A combination of different methodologies is used in our research. We mostly rely on classical molecular biology and cellular biology techniques. Cell culture is widely used and we also are using two animal models, mice and the nematode C.elegans.

Publications

10 25 50
 
Description Network of Excellence
Amount £140,000 (GBP)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 04/2006 
End 04/2011
 
Description Wellcome Trust Project Grant (Auxiliary factors for microRNA processing)
Amount £197,449 (GBP)
Funding ID 084057 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2008 
End 05/2011
 
Description EURASNET Network of Alternative Splicing 
Organisation Sixth Framework Programme (FP6)
Department European Alternative Splicing Network (EURASNET)
Country United Kingdom 
Sector Academic/University 
PI Contribution My lab has been part of EURASNET, which is the Alternative Splicing Network of Excellence funded by the Framework 6 Programme (FP6) of the European Union. The network aims to explain the mechanisms of alternative splicing and the interference with other regulatory processes; establish a communication platform among researchers; support Young Investigators to establish new research groups; and raise awareness of the importance of alternative splicing among clinicians, policy makers and the general public.
Collaborator Contribution We contributed Research projects to this Network and participated in an Annual meeting to exchange results and decide future directions of this Network
Impact Several publications have arisen as a result of this collaboration
Start Year 2006