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

Funding Summary

In PWS, a cluster of small nucleolar RNAs (snoRNAs), the SNORD116 cluster, appears to be of critical importance, but the SNORD116 targets have yet to be identified. Dr. Carmichael and his team have engineered neurons that mimic naturally-occurring PWS deletions and are using them to look for alterations in gene expression and regulation. In year 2 of the project, the researchers will generate and validate a detailed RNA expression signature of PWS neurons using these cellular models. Importantly, this work will also include detailed examination of differences in patterns of pre-mRNA splicing in PWS neurons and their connection to observed pathologies, since preliminary work has suggested interesting alterations in RNA processing events.


 

Lay Abstract

We are interested in learning the molecular underpinnings of Prader-Willi Syndrome. This disorder is the result of deletions of a region of the paternal chromosome 15 that expresses a number of RNAs that lack the potential to express protein products. In particular, a cluster of small nucleolar RNAs (snoRNAs), the SNORD116 cluster, appears to be of critical importance. However, no one has been able so far to identify the SNORD116 targets. To begin to address this issue we have generated isogenic pairs of neurons that mimic naturally-occurring PWS deletions (one with a paternal deletion spanning from the imprinting center to IPW and another
only deleting the paternal SNORD116 cluster) and are using them to look for alterations in gene expression and regulation using high depth next generation RNA sequencing. In year 2 of the project we will generate and validate a detailed transcriptomic signature of PWS neurons using these cellular models. Importantly, this work will also include detailed examination of differences in patterns of pre-mRNA splicing in PWS neurons and their connection to observed pathologies, since preliminary work has suggested interesting alterations in RNA processing events.

Funded Year:

2021

Awarded to:

Gordon Carmichael, Ph.D

Amount:

$64,800

Institution:

University of Connecticut

Researcher:

Gordon Carmichael, Ph.D

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