Institute for Cell Biology, School of Biological Sciences, The University of Edinburgh, Edinburgh, Scotland.
Institute of Biochemistry and Biophysics PAS, Warszawa, Poland.
Nat Commun. 2024 Nov 30;15(1):10427. doi: 10.1038/s41467-024-54573-8.
In the snoRNA host gene SNHG14, 29 consecutive introns each generate SNORD116, and 48 tandem introns encode SNORD115. Loss of SNORD116 expression, but not of SNORD115, is linked to the neurodevelopmental disease Prader-Willi syndrome. SNORD116 and SNORD115 resemble box C/D small nucleolar RNAs (snoRNAs) but lack known targets. Both were strongly accumulated during neuronal differentiation, but with distinct mechanisms: Increased host-gene expression for SNORD115 and apparent stabilization for SNORD116. For functional characterization we created cell lines specifically lacking the expressed, paternally inherited, SNORD115 or SNORD116 cluster. Analyses during neuronal development indicates changes in RNA stability and protein synthesis. These data suggest that the loss of SNORD116 enhances some aspects of developmental timing of neuronal cells. Altered mRNAs include MAGEL2, causal in the PWS-like disorder Schaaf-Yang syndrome. Comparison of SNORD115 and SNORD116 mutants identifies small numbers of altered mRNAs and ncRNAs. These are enriched for functions potentially linked to PWS phenotypes and include protocadherins, which are key cell signalling factors during neurodevelopment.
在 snoRNA 宿主基因 SNHG14 中，29 个连续的内含子各自产生 SNORD116，而 48 个串联内含子编码 SNORD115。SNORD116 表达的丧失，但不是 SNORD115 的丧失，与神经发育疾病普拉德-威利综合征有关。SNORD116 和 SNORD115 类似于框 C/D 小核仁 RNA（snoRNA），但缺乏已知的靶标。两者在神经元分化过程中都强烈积累，但机制不同：SNORD115 的宿主基因表达增加，而 SNORD116 的表观稳定性增加。为了进行功能表征，我们专门创建了缺失表达的、父系遗传的 SNORD115 或 SNORD116 簇的细胞系。在神经元发育过程中的分析表明 RNA 稳定性和蛋白质合成发生了变化。这些数据表明，SNORD116 的缺失增强了神经元细胞发育时间的某些方面。改变的 mRNAs 包括 MAGEL2，它是 Schaaf-Yang 综合征等 PWS 样疾病的致病基因。对 SNORD115 和 SNORD116 突变体的比较确定了少数改变的 mRNAs 和 ncRNAs。这些富含与 PWS 表型相关的功能，包括原钙粘蛋白，它们是神经发育过程中关键的细胞信号因子。
