Current evidence suggests that most Prader-Willi syndrome (PWS) traits result from loss of paternally inherited SNORD116 gene group. SNORD116 belong to a class of small nucleolar RNAs (snoRNAs), which are involved in modification of other RNA species. snoRNAs act as guides to define sites of target RNA modification by partner enzymes. Typically, a snoRNA would recognize its target by sequence complementarity. However, a number of snoRNAs including SNORD116 group do not appear to display any obvious sequence complementarity to typical snoRNA targets, indicating that they might influence other targets including mRNA to fine-tune protein expression in distinct cell types. Until recently, identification of RNA-RNA interactions was hampered by lack of relevant experimental techniques. Here, we propose to use a newly developed methodology that allows unbiased interrogation of cellular RNA-RNA interactions to uncover RNA targets of SNORD116, shining light on molecular mechanisms underlying Prader-Willi syndrome. We envision that identifying SNORD116 targets will also help to define new downstream drug targets and cause a shift in the focus of PWS therapeutic approaches
Research Outcomes: Project Summary
Lack of SNORD116 expression is considered the major cause of Prader-Willi syndrome. In contrast to canonical snoRNAs, SNORD116 is predominantly expressed in the brain and displays no apparent complementarity to rRNAs. Orphan snoRNAs were proposed to target other types of RNA and to have roles that extend beyond rRNA decoration. Bioinformatic prediction of snoRNA targets is unreliable due the fact that the base-pairing region is relatively short and tolerates mismatches. Thus, identification of snoRNA targets requires an unbiased transcriptome-wide experimental approach. We remain committed to development of such techniques and applying them to cell lines expressing snoRNAs of the Prader-Willi critical region. Defining targets of SNORD116 and other PWS locus orphan snoRNAs will lay grounds for focused mechanistic studies, ultimately leading to improved understanding of pathophysiological processes giving rise to the complex PWS phenotype. Detailed knowledge of PWS molecular pathology is a requisite for development of effective treatment for this complex neurodevelopmental condition.
Research Outcomes: Publications
Neuronal differentiation induces SNORD115 expression and is accompanied by post-transcriptional changes of serotonin receptor 2c mRNA. Bratkovič T, Modic M, Camargo Ortega G, Drukker M, Rogelj B . Scientific Reports. 2018 Mar 23;8(1):5101.
Tomaz Bratkovic, PhD
University of Ljubljana, Slovenia