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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 and biophysical 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, 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 mechanisms and biological roles of regulated alternative splicing in vascular smooth muscle cells (collaboration with Sanjay Sinha, Cambridge Stem Cell Institute, and Helle Jørgensen, Dept. Medicine). We have discovered a "master regulator" of alternative splicing in smooth muscle cells via association of its gene with superenhancers in smooth muscle tissues. This protein regulates alternative splicing of numerous genes important for smooth muscle function including the transcription factor myocardin. We also collaborate with Martin Turner (Babraham Institute) on post-transcriptional regulation by PTBP proteins in lymphoid cells (ref. 8).

The lab is currently funded via the Wellcome Trust 2018-2023 and British Heart Foundation (2016-18). 

Lab members: Current: Erick Eidy, Clare Gooding, Aishwarya Jacob, Elisa Monzon-Casanova (Babraham Institute), Anna Git (independent Senior Research Associate: http://www.cambridgecancercentre.org.uk/users/dr-anna-git)

Former: Selina Wang, Miguel Coelho, Peter Whitfield, Miriam Llorian, Dipen Rajgor, Adrian Buckroyd

Key publications:

1. M. Llorian, C. Gooding, N. Bellora, M. Hallegger, A. Buckroyd, X. Wang, D. Rajgor, M. Kayikci, J. Feltham, J. Ule, E. Eyras, C.W.J. Smith. The alternative splicing program of differentiated smooth muscle cells involves concerted non-productive splicing of post-transcriptional regulators. Nucleic Acids Research (2016) doi: 10.1093/nar/gkw560

2.  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

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.

8. Elisa Monzón-Casanova, Michael Screen, Manuel D. Díaz-Muñoz, Richard Coulson,Sarah E. Bell, Greta Lamers, Michele Solimena, Christopher W.J. Smith and Martin Turner. (2018) The RNA binding protein PTBP1 is necessary for B cell selection in germinal centers. Nature Immunology 19, 267-  DOI: 10.1038/s41590-017-0035-5