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Smooth muscle specific alternative splicing: super-enhancers point the way

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• Alternative splicing (AS) is a key mechanism of gene regulation, affecting the majority of human genes. Dysregulation of AS leads to human disease, but therapeutic manipulation of AS has also proven to be effective for treatment of disease. • We are interested in how the AS splicing programme is regulated in vascular smooth muscle cells, which show phenotypic plasticity and can interconvert between differentiated contractile and synthetic proliferative states in association with vascular disease. We have previously characterized the roles of RNA binding proteins such as PTBP1 and MBNL1 in regulating some smooth muscle AS events, but levels and activity of these proteins are not sufficient to explain regulation of the smooth muscle splicing programme. • By identifying RNA binding protein genes that are associated with transcriptional super-enhancers in smooth muscle tissues, we have identified an RNA binding protein that regulates numerous smooth muscle AS events. Among its targets is an exon that determines the activity of the key smooth muscle transcription factor myocardin, consistent with the suggestion that our new RNA binding protein is a “master regulator” of AS in smooth muscle cells.

This talk is part of the Cambridge Cardiovascular Seminar Series series.

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