Research
My group is interested in the molecular mechanisms of alternative pre-mRNA splicing. Alternative splicing is a key post-transcriptional mechanism for regulation of gene expression, allowing individual genes to generate multiple functionally distinct protein isoforms in a cell-type specific manner. Mis-regulation of splicing programmes is frequently associated with disease. For example, mutations in the RNA binding protein RBM20 lead to misregulated splicing in cardiomyocytes leading to dilated cardiomyopathy.
One of our major interests is in the regulated programmes of alternative splicing that occur during development and differentiation/dedifferentiation of vascular smooth muscle cells. We aim to define the critical RNA binding proteins that determine the VSMC-specific splicing programmes, to decipher the mechanisms by which they influence splicing outcomes, and also to understand the contribution of the regulated alternative splicing programmes to cell phenotype in health and disease.
Publications
Erick E. Nakagaki-Silva, Clare Gooding, Miriam Llorian, Aishwarya Griselda Jacob, Frederick Richards, Adrian Buckroyd, Sanjay Sinha & Christopher W.J. Smith. Identification of RBPMS as a mammalian smooth muscle master splicing regulator via proximity of its gene with super-enhancers. eLife 8:e46327 (2019)
The alternative splicing program of differentiated smooth muscle cells involves concerted non-productive splicing of post-transcriptional regulators. Llorian M, Gooding C, Bellora N, Hallegger M, Buckroyd A, Wang X, Rajgor D, Kayikci M, Feltham J, Ule J, Eyras E, Smith CW. Nucleic Acids Res. 2016 Oct 14;44(18):8933-8950.
Generation of functionally distinct isoforms of PTBP3 by alternative splicing and translation initiation. Tan LY, Whitfield P, Llorian M, Monzon-Casanova E, Diaz-Munoz MD, Turner M, Smith CW. Nucleic Acids Res. 2015 Jun 23;43(11):5586-600.
Nuclear matrix protein Matrin3 regulates alternative splicing and forms overlapping regulatory networks with PTB. Coelho MB, Attig J, Bellora N, König J, Hallegger M, Kayikci M, Eyras E, Ule J, Smith CW. EMBO J. 2015 Mar 4;34(5):653-68.
MBNL1 and PTB cooperate to repress splicing of Tpm1 exon 3. Gooding C, Edge C, Lorenz M, Coelho MB, Winters M, Kaminski CF, Cherny D, Eperon IC, Smith CW. Nucleic Acids Res. 2013 May;41(9):4765-82.
Decoding muscle alternative splicing. Llorian M, Smith CW. Curr Opin Genet Dev. 2011 Aug;21(4):380-7.
Position-dependent alternative splicing activity revealed by global profiling of alternative splicing events regulated by PTB. Llorian M, Schwartz S, Clark TA, Hollander D, Tan LY, Spellman R, Gordon A, Schweitzer AC, de la Grange P, Ast G, Smith CW. Nat Struct Mol Biol. 2010 Sep;17(9):1114-23.
