A new method and tools to map functional interactions of spliceosomal components accurately captures known, and identify new physical and functional associations important for health and disease.

The method can be used to infer targets for alternative splicing regulation, and to study the effects on splicing of compounds directed to altered, or disease-associated splicing events.

Technology:

Splicing in general, and alternative splicing in particular are crucial for the normal development and physiology of the cells/organisms, and alterations of these are more and more often found linked to a panoply of different human diseases, including cancers. The spliceosome itself (the complex molecular machinery responsible for splicing) is also the target of some natural compounds that display antitumor activities. Some powerful tools have been developed for the identification of novel regulators of cell proliferation or apoptosis (both fundamental cancer processes), but they easily fail to capture aspects of the physiological regulation of alternative splicing that are relevant for disease. Thus, scientist at CRG have developed a methodology for the identification of novel cancer drug targets based on: (i) systematically knocking down all the known components of the splicing machinery and closely related genes (more than 300); (ii) determining the effect of each of such perturbations on each and every event of a set of carefully selected alternative splicing events relevant for cell proliferation and apoptosis; and (iii) using the information gathered to computationally reconstruct a network of functional interactions using tools developed for the purpose. This greatly facilitates the identification of associations between regulatory factors involved, e.g. in: (a) general or specific alternative splicing events; (b) the connection with particular metabolic pathways; or (c) the response to internal or external perturbations such as the administration of drugs or other compounds. Thus, potentially relevant and in many cases yet unidentified biological drug targets can be inferred from the network, and the effects of their perturbation tested (e.g. using drugs). The final aim being, the discovery of new targets and compounds against them that alter relevant splicing events, and can be used for the treatment of cancers or other human diseases.

Advantages:

• The method captures aspects of the physiological regulation of alternative splicing where others may fail
• It may be used, both for drug target identification, and for testing the effect of target modulation with drugs or other compounds in diseases associated with alternative splicing
• Set up for the study of cancer-relevant alternative splicing events – the genes studied can be adapted to deliver networks of interactions relevant in any biological and pathological context
• Developed by one of the leading experts in the field of splicing

References:

Papasaikas, P. et al. (2015) Functional Splicing Network Reveals Extensive Regulatory Potential of the Core Spliceosomal Machinery. Molecular Cell 57, 7–22.

Tejedor, JR. et al. (2015) Genome-Wide Identification of Fas-CD95 Alternative Splicing Regulators Reveals Links with Iron Homeostasis. Molecular Cell 57, 23-38.