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Chris Smith

Regulation of alternative pre-mRNA splicing

Alternative pre-mRNA splicing allows individual genes to encode large numbers of functionally distinct proteins, and is a key mechanism that allows the generation of proteomes with a complexity that far exceeds the number of genes.  Our lab focuses on understanding the mechanisms responsible for regulated programmes of alternative splicing.  Our approaches include molecular dissection of individual model alternative splicing events, using cell culture and in vitro biochemical approaches to analyze the RNA-RNA, protein-RNA and protein-protein interactions responsible for regulating splicing complex assembly at regulated exons. These molecular approaches are complemented by transcriptomic, ribonomic, proteomic and computational techniques, which allow us to take a global view of alternative splicing and the underlying regulatory networks.  Our main current biological interests involve the regulation of alternative splicing in vascular smooth muscle cells, and lymphoid cells (collaboration with Martin Turner, Babraham Institute).  We are also interested in the direct functional consequences of alternative splicing.  In particular, many splicing factors and regulators are themselves regulated by "non-productive" alternative splicing events.

Lab members: Adrian Buckroyd, Selina Wang, Miguel Coelho, Peter Whitfield, Clare Gooding, Miriam Llorian, Dipen Rajgor, Nadine Law, Elisa Monzon-Casanova (Babraham Institute)

Key publications:

1.  M. Coelho, J. Attig, N. Bellora, J. König, M. Hallegger, M. Kayikci, E. Eyras, J. Ule, C.W.J. Smith. Nuclear Matrix Protein Matrin3 regulates alternative splicing and forms overlapping regulatory networks with PTB.  EMBO Journal (2015DOI 10.15252/embj.201489852

2. I. Mickleburgh, P. Kafasla, D. Cherny, M. Llorian, S. Curry, R.J. Jackson, C.W.J. Smith. The organization of RNA contacts by PTB for regulation of FAS splicing. Nucleic Acids Res. (2014) doi: 10.1093/nar/gku519

3. Gooding, C.,  Edge, C., Coelho, M.B., Lorenz, M. Winters, M., Kaminski, C.F., Cherny, D., Eperon, I.C. & Smith, C.W.J. MBNL1 and PTB cooperate to repress splicing of Tpm1 exon 3. Nucleic Acids Res. 41, 4765-4782 (2013)

4. Llorian, M., and Smith, C.W.J. Decoding muscle alternative splicing (2011). Curr. Op. Genet. Dev., 21, 380-387

5. Llorian, M., Schwartz, S., Clark, T.A., Hollander, D., Tan, L.Y., Spellman, R., Gordon, A., Schweitzer, A.C., la Grange, P., Ast, G., and Smith, C.W.J. (2010). Position-dependent alternative splicing activity revealed by global profiling of alternative splicing events regulated by PTB. Nat Struct Mol Biol 17, 1114-1123.

6. McGlincy, N.J., and Smith, C.W.J. (2008). Alternative splicing resulting in nonsense-mediated mRNA decay: what is the meaning of nonsense? Trends Biochem Sci 33, 385-393.

7. Spellman, R., Llorian, M., and Smith, C.W.J. (2007). Crossregulation and functional redundancy between the splicing regulator PTB and its paralogs nPTB and ROD1. Mol Cell 27, 420-434.