Functional Consequences of Mammalian-Specific Alternative Splicing Events in RNA Binding Proteins

Barbara Vivash Award in Molecular Genetics
Dr. Serge Gueroussov
Broad Institute, MIT and Harvard
Friday, February 16, 2018 - 2:00pm
CCBR Red Room
Special Seminar
Alternative splicing (AS) patterns diverged rapidly in vertebrates, but the functions of most species- and lineage-specific isoforms remain unknown. Using a combination of targeted and transcriptome-wide analyses, I characterized the mammalian-specific isoforms of multiple RNA binding proteins. I showed that mammalian-specific AS in the PTBP1 gene alters its activity, and engineered AS of the orthologous exon in chicken is sufficient to induce mammalian-like regulatory changes. AS of this exon during neurogenesis was found to significantly impact differentiation timing in mice. Subsequent analysis of all mammalian-specific exons revealed they are enriched in glycine/tyrosine-rich disordered domains, such as those of HNRNPA and D genes. Evolution of skipping involved formation of intramolecular RNA duplexes. At the protein level, inclusion of such exons facilitates higher-order assemblies on substrate pre-mRNAs required for AS regulation. This work demonstrates how splice isoform evolution in RNA binding proteins can impact development and expand the regulatory capabilities of mammalian cells.
Dr. Leah Cowen
Department of Molecular Genetics