Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
Clare Gooding
Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
Miriam Llorian
Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom; Francis Crick Institute, London, United Kingdom
Aishwarya G Jacob
Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom; Anne McLaren Laboratory, Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
Frederick Richards
Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
Adrian Buckroyd
Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
Sanjay Sinha
Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom; Anne McLaren Laboratory, Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
Alternative splicing (AS) programs are primarily controlled by regulatory RNA-binding proteins (RBPs). It has been proposed that a small number of master splicing regulators might control cell-specific splicing networks and that these RBPs could be identified by proximity of their genes to transcriptional super-enhancers. Using this approach we identified RBPMS as a critical splicing regulator in differentiated vascular smooth muscle cells (SMCs). RBPMS is highly down-regulated during phenotypic switching of SMCs from a contractile to a motile and proliferative phenotype and is responsible for 20% of the AS changes during this transition. RBPMS directly regulates AS of numerous components of the actin cytoskeleton and focal adhesion machineries whose activity is critical for SMC function in both phenotypes. RBPMS also regulates splicing of other splicing, post-transcriptional and transcription regulators including the key SMC transcription factor Myocardin, thereby matching many of the criteria of a master regulator of AS in SMCs.
