SNORD116 and SNORD115 change expression of multiple genes and modify each other's activity

• SNORD116 and SNORD115 are C/D box snoRNAs not expressed in Prader–Willi syndrome.
• SNORD116 changes expression levels of multiple genes, not alternative splicing.
• SNORD115 affects SNORD116 action on gene expression.
• This is the first example of two SNORDs acting synergistically, which correlates with clinical findings.

The loss of two gene clusters encoding small nucleolar RNAs, SNORD115 and SNORD116 contribute to Prader–Willi syndrome (PWS), the most common syndromic form of obesity in humans. SNORD115 and SNORD116 are considered to be orphan C/D box snoRNAs (SNORDs) as they do not target rRNAs or snRNAs. SNORD115 exhibits sequence complementarity towards the serotonin receptor 2C, but SNORD116 shows no extended complementarities to known RNAs. To identify molecular targets, we performed genome-wide array analysis after overexpressing SNORD115 and SNORD116 in HEK 293T cells, either alone or together. We found that SNORD116 changes the expression of over 200 genes. SNORD116 mainly changed mRNA expression levels. Surprisingly, we found that SNORD115 changes SNORD116's influence on gene expression. In similar experiments, we compared gene expression in post-mortem hypothalamus between individuals with PWS and aged-matched controls. The synopsis of these experiments resulted in 23 genes whose expression levels were influenced by SNORD116. Together our results indicate that SNORD115 and SNORD116 influence expression levels of multiple genes and modify each other activity.