UNLEASHing the Secrets of Splicing

Cells use editing tools to skip or rearrange information stored in DNA. Thanks to a 10-million-euro ERC Synergy Grant co-financed by ERC and UKRI, researchers have launched a project to study how this machinery can be controlled with molecular precision, which has the potential to revolutionize biomedical research and eventually treat human disease.

Splicing

Imagine sitting down to watch a film for a second time, but the story takes a surprising turn, for example a new scene or a particular voiceover. You might realize that rather than the theatrical version you saw in the first place, this is a Director’s Cut. The movie producers have created not just one, but two versions of the same film, each with its own unique scenes and storyline.

The same thing is happening – at the molecular scale – inside every human cell. Cells are like eccentric filmmakers, using a process known as alternative splicing as their creative tool. Just how movie producers use an editing toolbar to rewind, speed up or cut a scene entirely, cells use their editing tools to swap, skip or include specific DNA segments in the messenger RNA. This ability allows cells to alter gene expression or create slightly different versions of a protein with unique functions.

Humans have roughly 20 thousand genes within our genomes, but thanks to alternative splicing, cells can make more than 100 thousand. This expanded catalogue of proteins helps cells both adapt to changing environments and carry out more complex functions. It is thought that almost 95 % of human genes undergo alternative splicing of some sort.

Potential of Unleash

Knowledge of alternative splicing can be used to reveal new therapeutic targets. To treat diseases that were previously considered incurable, both antisense oligonucleotides (nusinersen) and small molecules (risdiplam) that modulate alternative splicing of the gene SMN2 have reached the clinic for the treatment of spinal muscular atrophy, one of the leading causes of infant mortality. Despite the emerging success of splicing-based therapies, the mechanistic understanding of how small molecule drugs can modulate alternative splicing remains very limited. Small molecule drugs have distinct advantages as therapeutics as they can be administered orally and pass-through cell membranes to reach the cell nucleus, where alternative splicing takes place. To accelerate the discovery of therapeutic targets for other diseases previously considered untreatable, researchers require new experimental tools and methods to study the underlying biological mechanisms as well as the splice code involved.