Studies of RNA splicing continue to provide crucial insight into the mechanisms underlying RNA processing, as well as the downstream consequences for healthy and malignant cell states. In recent years it has become clear that both core components of the spliceosome as well as other splicing factors are frequently dysregulated across a wide range of human diseases. This includes altered gene expression levels, but also mutations conferring either gain- or loss-of-function phenotypes.
The focus of our research is to (i) study the factors and mechanisms affecting RNA processing, (ii) investigate the downstream molecular and cellular effects of aberrant RNA splicing, and (iii) understand how RNA mis-regulation contributes to human diseases. The ultimate aim is to use this information to explore new therapeutic avenues in disorders affected by transcriptomic alterations.
Our work is largely centered on abnormal as well as basal splicing in the context of cancer. For example, we’re using RNA-sequencing data from the TCGA data to conduct a large-scale pan-cancer characterization of RNA splicing in tumor biopsies compared to peri-tumoral samples. One of the striking findings was an unexpectedly large degree of intron retention, which was observed across multiple types of cancers from different tissues of origin. Overall splicing efficiency doesn’t seem to be compromised, however, and this cancer-related mis-splicing occurs even in the absence of any obvious changes to the splicing machinery.
In addition to studying the proteins involved in splicing, we’re also interested in the role of small nuclear RNAs (snRNAs), which are part of the spliceosomal snRNP complexes. These non-coding RNAs are best known for playing basal roles in splicing catalysis, and are not typically studied in the context of splicing regulation or dysregulation in disease. However, our findings indicate that they may play an unexpectedly complex role in RNA processing.