With the completion of the human genome project, it has become clear that the sheer number of genes cannot account for the complexity of the human proteome. Among several proposed mechanisms, alternative pre-mRNA splicing is considered to be one of the most efficient and widespread avenues to generate multiple protein isoforms from individual genes. Current estimates indicate that over 90% of all human genes undergo alternative splicing, thus greatly increasing the coding potential of our genome. It is also appreciated that many alternative pre-mRNA processing changes associate with most human diseases, such as cancer. The multitude of cancer-specific mRNA isoform generation raises the important question to what degree the different flavors of gene expression are beneficial for tumor growth. Research in the Hertel laboratory focuses on elucidating the mechanisms of splice site selection with the long-term goal to decipher splicing networks and to establish a splicing code that permits alternative splicing predictions based on sequence analysis. We have a record of developing novel biochemical assays to analyze alternative splicing and now routinely incorporate bioinformatics approaches to verify and test the generality of our findings with the aid of genome-wide high throughput analyses. This cross-disciplinary approach has helped us to successfully highlight the importance of RNA splicing elements in dictating splice site selection and exon choice. Our systems approach examines methodically how the combination of RNA splicing elements influences splice site selection, with the ultimate goal to faithfully predict alternative splicing changes in disease models.
Our research focuses on the following topics:
- Determine the biochemical steps that lead to splice site pairing and understand the combinatorial control of exon definition.
- Determine he influence of alternative pre-mRNA processing on colon cancer progression.
- Determine the mechanisms of splice site activation and repression.
- Determine the dynamics of gene expression from pre-mRNA synthesis through RNA processing in the nucleus to translation and mRNA degradation in the cytoplasm.