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C/D box snoRNAs have been mainly implicated in targeting the methylase fibrillarin to rRNA, causing its 2’-O-methylation. However, about half of known SNORDs have no identifiable RNA targets, e.g. SNORD116 and SNORD115, whose loss leads to Prader-Willi syndrome (PWS). Recent studies showed non-canonical function of SNORDs in pre-mRNA alternative splicing, a fundamental process of human gene-regulation and proteome diversity. We found that about a quarter SNORDs including SNORD116 are also found with spliceosomes, in non-canonical complexes devoid of the methylase fibrillarin, and could thus have other functions. We also devised a method to knock-down SNORDs using mixed oligonucleotides and determined that most target genes for SNORD116 regulate microexons, whose deregulation is a hallmark of autism, a feature of PWS. We will test the hypothesis that by forming a novel snoRNP, SNORD116 promotes distinct sets of microexons by masking splicing regulatory elements in their pre-mRNA, regulating a gene program influencing vesicular transport. This interdisciplinary collaboration combines in a synergistic way the complementary expertise of the Israeli and US PIs, who are specialists in RNP characterization and SNORD-dependent alternative splicing. We will test our hypothesis in two Specific Aims: 1. Characterize novel, fibrillarin-free protein complexes formed by SNORD116. 2. Determine snoRNA116 mode of function on its target genes. The proposed studies are innovative as alternative splicing of microexons has not been studied systematically, and significant as autism is a growing epidemic with unknown molecular cause. Testing the hypothesis that SNORD116 regulates microexons could help unveil the molecular mechanism, and lay the foundation for rational therapeutic approaches.
|Effective start/end date||10/1/18 → 9/30/22|
- US-Israel Binational Science Foundation
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- 1 Finished
10/1/18 → 9/30/22
Project: Research project