Splicing Regulation

RNA splicing is a post-transcriptional process where protein coding exons in the initial pre-mRNA are joined together, while the intervening intronic sequences are spliced out. The splicing process is highly complex and is regulated by a large number of proteins. 

The splice sites are defined by relatively conserved sequences, which allows recognition by the spliceosome. However, splicing enhancer and silencer elements are necessary for the regulation of splicing. These are cis-acting elements binding splicing regulatory proteins, and these sites define the so-called splicing code, which determines the splicing outcome.

The alternative splicing which is the result of this dynamic regulation increases the number of proteins which can be encoded by the human genome and therefore is important for human complexity.

To be able to decipher the splicing code we did RNA binding studies and created a map of hnRNP A1 binding sites:

Global identification of hnRNP A1 binding sites for SSO-based splicing modulation                                                                                                                                                                         Bruun et al., BMC Biology, Jul 2016

And  based on in vivo binding studies, we developed a computational tool to predict binding of a large number of RNA binding proteins to RNA using only sequence input:

DeepCLIP: predicting the effect of mutations on protein–RNA binding with deep learning                                                                                                                                              Grønning et al., Nucleic Acids Research, Jun 2020

Exon Vulnerability 

Mutations in exonic splicing regulatory elements may affect the delicate regulation of RNA splicing, and it is widely accepted that such mutations can cause aberrant splicing and in some cases lead to disease. However, we have shown that not all exons are equally vulnerable to these mutations

Vulnerable exons, like ACADM exon 5, are highly dependent on maintaining a correct balance between splicing enhancers and silencers                                Holm et al., Human Mutation, Feb 2022

We developed the computational tool VulExMap to identify constitutive exons which are vulnerable to exonic splice mutations:

All exons are not created equal-exon vulnerability determines the effect of exonic mutations on splicing                                                                                                                  Holm et al., Nucleic Acids Research, May 2024