EAPSI: Characterizing the Gene Splicing Mechanisms of Three Developmental Events in Human and Mouse

Siboni Ruth B, Eugene OR

Investigators

Abstract

Numerous debilitating diseases, including breast cancer, Friedreich?s ataxia, â-thalassaemia, and others, are the direct result of errors in the regulatory process of mRNA splicing. The identification of splicing perturbations is important, but equally important is an understanding of the mechanisms by which these events are regulated. The purpose of this research is to characterize three recently uncovered splicing events that are perturbed in a debilitating disease, myotonic dystrophy. This work will be performed in collaboration with Dr. Masanori Takahashi and Dr. Masayuki Nakamori at the University of Osaka. This collaboration affords access to novel splicing data recently identified by Dr. Nakamori and will enable insight into previously unexplored splicing events. Appropriate splicing regulation is contingent on the interplay between splicing regulation proteins and their recognition sequences found on mRNA. One example of this relationship is demonstrated by the splicing regulator MBNL1, which regulates over 90 different transcripts. MBNL1 recognizes and binds GC elements located on target RNA. Once bound, MBNL1 can promote either exon inclusion or removal from the final mRNA transcript, depending cellular needs. However, the precise mechanisms that govern transcript response and sensitivity for MBNL1 levels are not fully understood. Recent data suggest that splicing targets of MBNL1 vary in the amount of MBNL1 needed for an appropriate regulatory response. To examine this idea further, Dr. Masayuki and I will use cell-based splicing assays to determine the MBNL1-sensitivity of three splicing events which have been recently implicated in disease. In doing so, we hope to further understand the role that MBNL1 regulation plays in splicing perturbations. This NSF EAPSI award is funded in collaboration with the Japanese Society for the Promotion of Science (JSPS).