Genomewide identification of mRNA sites of 2’-O methylation targeted by SNORD116 snoRNAs

Funding Summary

While we know the loss of SNORD116 (a gene that encodes many snoRNA molecules on Chromosome 15) leads to characteristics of PWS, we do not know how this exactly works. We need to understand how SNORD116 functions normally in order to understand why the loss of this region leads to PWS. It is likely that the snoRNAs in the SNORD116 region modify other RNAs, but the exact target genes are not yet known. Dr. Carmichael is an expert in RNA who has developed a new technique to detect and sequence the genes that these snoRNAs are modifying.

This study will help understand what is causing PWS on a molecular level by helping us understand how these critical PWS-region genes normally function, and in the future can help develop therapies that target the effects of the loss of SNORD116.

Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip. 

Watch the full webinar describing the 8 research projects funded in this grant cycle here


 

Lay Abstract

Prader-Willi syndrome results from deletion of a specific region of the paternal chromosome 15 in humans. This region expresses 29 similar RNA molecules called snoRNAs, which are all relatively short and lack the potential to encode any proteins.  snoRNAs of this type are generally thought to recognize and associate with target RNAs by base complementarity and direct the modification of specific residues by methylating the 2’-hydroxyls of ribose rings. Most cellular snoRNAs target ribosomal RNAs, but those from the Prader-Willi critical region (SNORD116s) do not and their targets are unknown. 

We have recently developed a powerful new method to identify genomewide sites of 2’-O methylation and propose to use this method to identify, for the first time, the actual targets of the SNORD116 snoRNAs.  For this work we have constructed an isogenic pair of stem cells, which differ only in whether they do or do not express RNAs from the PWS critical region. These will be compared by next generation sequencing methods for RNA expression profiles and also for sites of RNA 2’-O methylation.  The cells will also be differentiated into neurons and similar comparisons will be made. Together, these studies should offer us an unprecedented window into the molecular underpinnings of PWS.  

Funded Year:

2019

Awarded to:

Gordon Carmichael, Ph.D

Amount:

$54,000

Institution:

University of Connecticut

Researcher:

Gordon Carmichael, Ph.D

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