Role of non-methylating C/D box snoRNAs in Prader-Willi syndrome: Old dogs show new tricks

C/D box small nucleolar RNAs (SNORDs) are small noncoding RNAs, and their best-understood function is to target the methyltransferase fibrillarin to rRNA through base pairing between the SNORD and the rRNA. However, about half of the 267 human SNORDs have no predictable targets and are thus ‘orphan’. Loss or marked increase of SNORD expression is associated with numerous diseases such as Prader-Willi syndrome (PWS), Duplication 15q syndrome, several forms of cancer, and lipotoxicity. As most of the SNORDs involved in these diseases are orphan, they have likely molecular functions different form rRNA methylation.

Using a native nuclear fractionation scheme, we found that about 1/3 of all SNORDs are present in a fraction that is free of fibrillarin, demonstrating functions outside of rRNA methylation [1]. We refer to SNORDs that are not associated with fibrillarin as non-methylating SNORDs [2].

We showed for two of these SNORDs, SNORD27 and SNORD115 a role in pre-mRNA alternative splicing [1, 3]. SNORD115 is missing in Prader-Willi syndrome and its main function is to regulate the activity of the serotonin receptor 2C by controlling the ratio of two splicing isoforms [4]. The disruption of this regulation in PWS likely contributes to the hyperphagia. The splicing of the serotonin receptor 2C can be manipulated with oligonucleotides, leading to a reduction of food intake, which could be a therapeutic approach for PWS and shows the principle that SNORD-loss can be substituted [5]. Currently, we are analyzing the role of SNORD116, which is central to the etiology of PWS. More than 1/3 of SNORD116 is not associated with fibrillarin, indicating non-methylating functions. SNORD116 regulates alternative splicing and surprisingly mRNA stability, which explains numerous aspects of the syndrome.

In summary, SNORDs function outside the known role in rRNA methylation, by forming diverse RNPs lacking the methylase fibrillarin (non-methylating SNORDs). They bind to target mRNA and pre-mRNAs, where they change splicing and mRNA stability. These findings are significant, as SNORDs are highly expressed RNAs, for example the number of SNORD3 molecules in a cell is equal to the total number of all mRNAs, suggesting a strong role for SNORDs in gene expression.

[1]       M. Falaleeva, A. Pages, Z. Matuszek, S. Hidmi, L. Agranat-Tamir, K. Korotkov, Y. Nevo, E. Eyras, R. Sperling, S. Stamm, Dual function of C/D box snoRNAs in rRNA modification and alternative pre-mRNA splicing Proc Natl Acad Sci U S A 113 (2016) E1625-1634.

[2]       M. Falaleeva, J.R. Welden, M.C. Duncan, S. Stamm, C/D-box snoRNAs form methylating and non methylating ribonucleoprotein complexes: old dogs show new tricks, Bioessays 39 (2017).

[3]       S. Kishore, S. Stamm, The snoRNA HBII-52 regulates alternative splicing of the serotonin receptor 2C, Science 311 (2006) 230-232.

[4]       S. Stamm, S.B. Gruber, A.G. Rabchevsky, R.B. Emeson, The activity of the serotonin receptor 2C is regulated by alternative splicing, Hum Genet (2017).

[5]       Z. Zhang, M. Shen, P. Gresch, M. Ghamari-Langroudi, A.G. Rabchevsky, R.B. Emeson, S. Stamm, Oligonucleotide-induced alternative splicing of serotonin 2C receptor reduces food intake, EMBO Mol Med 8 (2016) 878-894.