Mechanism Of Snord115Overexpression In Snord116Knockout Mouse Model Of Prader-Willi Syndrome

Prader-Willi syndrome is a complex human hereditary disease of obesity. Latest reports have confirmed that Snord116is the most critical gene for PWS. A Snord116deletion (Snord116del) mouse model of PWS was established. We found an interesting phenomenon that Snord115was overexpressed in the non-neural tissue of Snordll6del mice. Previous studies showed that the transcription of PWS critical region starts from imprinting center upstream of protein coding gene Snrpn and extended as an-1000kb long transcript, the regulatory mechanism for Snord115, however, was not clear. In this study, the mechanism for Snord115overexpression was investigated. We proposed three hypotheses and tested them by analyzing the gene expression in the mouse model. The first hypothesis is that, the Snord115overpression is caused by increased efficiency of Snrpn initiation in knock-out mice. By comparing Snrpn expression in wild-type and knock-out mice, we found no support for this hypothesis.The second hypothesis is that, a novel promoter upstream of Snord115is activated in the non-neural tissue of Snord116knock-out mice. By examining the sequence upstream of Snord115, the presence of a novel promoter was ruled out. The third hypothesis is that, the Snord116region in the non-neural tissue can hinder the transcription of long transcript. The data indicate that the deletion region hinders the transcription of the long transcript. After deleting the region, the transcription gets more fluent, and Snord115can be expressed efficiently in the non-neural tissue. Elongation or termination factors may involve in this process. On the other hand, our data show that Snord115has a high copy number in the genome. In additional, through in vivo and in vitro experiments respectively, it is concluded that Snord115is extremely stable comparing with other mRNA so that it can accumulate to a high level in the cell. Due to these two mechanisms, Snord115is overexpressed in the non-neural tissue of the Snord116knock-out mice. Moreover, this study revealed that alternative termination of Snrpn is critical for the expression of the long non-coding RNA of the PWS region. A new and convenient technique to explore the mechanism of alternative termination is established for further research. Lastly, Snord115has the potential to be a biomarker identifying the brain injury.