Chris Smith

smithc

Regulation of alternative pre-mRNA splicing.

Alternative pre-mRNA splicing (AS) 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 AS programmes. 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. These molecular approaches are complemented by transcriptomic, proteomic and computational techniques, which allow us to take a global view of AS and the underlying regulatory networks. Our main current biological interests involve the mechanisms and biological roles of AS in vascular smooth muscle cells (collaboration with Sanjay Sinha, Cambridge Stem Cell Institute, and Helle Jørgensen, Department of Medicine). We have discovered a 'master regulator' of alternative splicing 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.​

Research objectives

  • Identify the key RNA binding proteins that determine cell-type specific alternative splicing in vascular smooth muscle cells.

  • Understand the detailed molecular mechanisms underpinning regulated alternative splicing.

  • Understand the contribution of alternative splicing programmes to cell-specific phenotypes.

Key publications

Yi Yang, Giselle Chi-ling Lee,  Erick Nakagaki-Silva, Yuling Huang, Matthew Peacey, Ruth Partridge, Clare Gooding, Christopher WJ Smith (2023). Cell-type specific regulator RBPMS switches alternative splicing via higher-order oligomerization and heterotypic interactions with other splicing regulators. Nucleic Acids Research. doi: 10.1093/nar/gkad652

Michael D. Barnhart, Yi Yang, Erick E. Nakagaki-Silva, Thomas H. Hammond, Mariavittoria Pizzinga, Clare Gooding, Katherine Stott, Christopher W.J. Smith (2022). Phosphorylation of the Smooth Muscle Master Splicing Regulator RBPMS Regulates its Splicing Activity. Nucleic Acids Res 50(20): 11895–11915. ​​​​doi: 10.1093/nar/gkac1048

Charlotte J. Wright, Christopher W.J. Smith, Chris D. Jiggins (2022). Alternative splicing as a source of phenotypic diversity. Nat Rev Genet 23: 697–710. doi: 10.1038/s41576-022-00514-4

Nakagaki-Silva EE, Gooding C, Llorian M, Jacob AG, Richards F, Buckroyd A, Sinha S, Smith CW (2019). Identification of RBPMS as a mammalian smooth muscle master splicing regulator via proximity of its gene with super-enhancers. eLife, 8:e46327. doi: 10.7554/eLife.46327

Monzón-Casanova E, Screen M, Díaz-Muñoz MD, Coulson RMR, Bell SE, Lamers G, Solimena M, Smith CWJ, Turner M (2018). The RNA-binding protein PTBP1 is necessary for B cell selection in germinal centers. Nat. Immunol., 19(3):267-278. doi: 10.1038/s41590-017-0035-5

Llorian M, Gooding C, Bellora N, Hallegger M, Buckroyd A, Wang X, Rajgor D, Kayikci M, Feltham J, Ule J, Eyras E, Smith CW (2016). The alternative splicing program of differentiated smooth muscle cells involves concerted non-productive splicing of post-transcriptional regulators. Nucleic Acids Res., 44(18):8933-8950. doi: 10.1093/nar/gkw560

Coelho MB, Attig J, Bellora N, König J, Hallegger M, Kayikci M, Eyras E, Ule J, Smith CW (2015). Nuclear matrix protein Matrin3 regulates alternative splicing and forms overlapping regulatory networks with PTB. EMBO J., 34(5):653-668. doi: 10.15252/embj.201489852

Gooding C, Edge C, Lorenz M, Coelho MB, Winters M, Kaminski CF, Cherny D, Eperon IC, Smith CW (2013). MBNL1 and PTB cooperate to repress splicing of Tpm1 exon 3. Nucleic Acids Res., 41(9):4765-4782. doi: 10.1093/nar/gkt168