Post-transcriptional regulation of gene expression in neuromuscular disease

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Project Summary Myotonic dystrophy (DM) is the most common form of muscular dystrophy, and leads to symptoms in all muscle types, in the form of skeletal muscle wasting, cardiac arrhythmias, and gastrointestinal dysfunction. A multi-systemic disease, DM also commonly affects the central nervous, endocrine, and reproductive systems. DM is caused by expanded CTG or CCTG repeats, which are transcribed into RNA, sequestering the Muscleblind- like (MBNL) RNA binding proteins and titrating them away from their normal mRNA targets. CUG repeat expression also leads to hyper-phosphorylation of the CUGBP/ ELAV-like factors (CELFs), resulting in CELF protein elevation. Dysregulation of MBNLs and CELFs causes hundreds of changes to the transcriptome, including many changes in alternative splicing. To date, the full spectrum of transcriptome changes in DM remains uncharacterized, and it is unknown whether MBNL and CELF perturbation can fully account for those changes. Furthermore, the molecular causes of only a few DM symptoms have been discovered. Another cellular process mediated by the MBNL proteins is RNA localization. Subcellular localization of RNA is important for numerous cellular and physiological processes, including cell motility, embryonic patterning, and synaptic function. However, our understanding of RNA localization remains restricted to a small subset of tran- scripts, and we lack a molecular parts list for how RNA localization is achieved. Identification of these players will reveal the extent to which RNA mis-localization contributes to pathology in DM and other diseases. Therefore, we will systematically characterize transcriptome changes in DM and assess the extent to which MBNL and CELF per- turbation can explain these changes in DM transcriptomes (Aim 1). We will define a parts list for RNA localization, including cis- and trans- elements, and elucidate how these players control subcellular distribution of RNAs (Aim 2). We will study how changes in all steps of gene expression, including splicing, RNA localization, and translation, may be linked to DM phenotypes, and develop therapeutic approaches to correct these changes (Aim 3). Together, completion of this work will further our understanding of the molecular changes in DM, a paradigm for diseases of RNA toxicity, lay the groundwork for better understanding RNA localization, and help connect these molecular events to physiology. PUBLIC HEALTH RELEVANCE: DM is the most common form of muscular dystrophy, and is a paradigm for a class of diseases caused by RNA toxicity. Understanding molecular changes in DM and linking them to phenotypes will help us understand how disease phenotypes arise and how they can be treated.