The SNORD genes are known to be very important in PWS, but there is a lack of appropriate tools to study the target and function of these genes. Dr. He and his team have developed two new methods that can map the targets of the SNORD genes. They will apply these new methods to mouse models and human cell lines with a deficiency in PWS-encoded SNORDs to better understand the function of the SNORD genes and help us understand how loss of these genes leads to the characteristics of PWS.
Lay Abstract
Prader-Willi syndrome (PWS) is a neurodevelopmental disorder causally linked to defects in a genomic region that harbors C/D box small nucleolar RNA (SNORD) genes, particularly SNORD115 and SNORD116. SNORDs bind target RNAs and facilitate sequence-specific modifications known as 2'-O-methylation (Nm). However, elucidating the specific targets and functions of the PWS-encoded SNORDs (SNORD115/SNORD116) has been challenging due to the lack of effective research tools. To identify the target RNAs of PWS-encoded SNORDs and their corresponding Nm modification sites, it is essential to employ methods that accurately map RNA-RNA interactions and Nm modifications. In our phase I studies, we implemented two innovative methods that enable transcriptome-wide mapping of RNA-RNA interactions and Nm modifications. Our results revealed no overlap between SNORD116 targets and SNORD116-dependent Nm sites, suggesting additional functions of SNORD116 beyond mRNA modification. Interestingly, we identified strong interactions between SNORD116 and U1 in both human and mouse models. U1 is a critical non-coding RNA that regulates gene expression. In the subsequent phase of our research, we aim to investigate how the absence of SNORD116 potentially affects the functions of U1 in PWS model cells. These insights will open new possibilities and directions on how the dysfunction of SNORD116 contributes to the pathogenesis of PWS.