Gene expression in higher eukaryotes is dominated by two regulatory processes. The first is quantitative control of expression, which is predominantly achieved by transcription. This second is qualitative control, the identity of what is ultimately expressed, which is achieved by RNA splicing. Our research group aims to expand our understanding of how gene expression is regulated, and use this knowledge to develop a new generation of therapeutics. Underpinning these developments is creating a molecular toolbox of approaches to interrogate biology not possible with conventional methods.
Bio-orthogonal chemistry enables the reaction of two reagents to occur in the presence of a myriad of other reactive groups present in the cellular environment. We are developing new bio-orthogonal reactions that are fast, produce a single product (i.e., no regioisomers) and can be used in the presence of other bio-orthogonal reagents. These reactions are being used to prepare protein and nucleic acid-based bioconjugates and as chemical probes in cell biology.
Regulating transcription (i.e., the synthesis of an RNA sequence derived from a DNA template) is the fundamental process by which nature controls the early stages of gene expression, and ultimately cellular function. The selective recognition of double-stranded DNA sequences by transcription factors is used by cells to respond to environmental changes, regulating which genes are switched on or off, and is used to control differentiation from one cell type into another. Dysregulation of transcription is also a prominent feature of many neurodegenerative disease and cancer. An enduring challenge in drug discovery is the design of synthetic transcription factors that correct aberrant transcription – i.e., turn on or off – of diseased genes. The group is developing a new generation of synthetic transcription factors that selectively recognise DNA sequences and modulate the expression of target genes.
RNA splicing is an extraordinary process that generates protein diversity (i.e., up to 150 000 proteins) from approximately 20,000 human genes. The outcome of splicing is controlled by the spliceosome, a multi-megadalton molecular machine which removes non-protein-coding introns from pre-mRNA and joins protein-coding exons to produce mature mRNA and a lariat structure (Figure 1). Almost all our protein-coding genes express more than one mature mRNA sequence (isoform); many of which encode unique proteins. The corresponding protein isoforms oftendiffer in only small blocks of RNA sequence, yet these small changes completely alter the function of these proteins. We are developing new molecular approaches to study how cells use splicing to control gene expression. These approaches are also being harnessed for the development of therapeutics which alter the outcome of splicing in neurodegenerative diseases and cancer.