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. 2014 Sep 23:4:6445.
doi: 10.1038/srep06445.

Differential regulation of non-protein coding RNAs from Prader-Willi Syndrome locus

Chenna R Galiveti  1 , Carsten A Raabe  2 , Zoltán Konthur  3 , Timofey S Rozhdestvensky  2
Affiliations

Differential regulation of non-protein coding RNAs from Prader-Willi Syndrome locus

Chenna R Galiveti et al. Sci Rep. .

Abstract

Prader-Willi Syndrome (PWS) is a neurogenetic disorder caused by the deletion of imprinted genes on the paternally inherited human chromosome 15q11-q13. This locus harbours a long non-protein-coding RNA (U-UBE3A-ATS) that contains six intron-encoded snoRNAs, including the SNORD116 and SNORD115 repetitive clusters. The 3'-region of U-UBE3A-ATS is transcribed in the cis-antisense direction to the ubiquitin-protein ligase E3A (UBE3A) gene. Deletion of the SNORD116 region causes key characteristics of PWS. There are few indications that SNORD115 might regulate serotonin receptor (5HT2C) pre-mRNA processing. Here we performed quantitative real-time expression analyses of RNAs from the PWS locus across 20 human tissues and combined it with deep-sequencing data derived from Cap Analysis of Gene Expression (CAGE-seq) libraries. We found that the expression profiles of SNORD64, SNORD107, SNORD108 and SNORD116 are similar across analyzed tissues and correlate well with SNORD116 embedded U-UBE3A-ATS exons (IPW116). Notable differences in expressions between the aforementioned RNAs and SNORD115 together with the host IPW115 and UBE3A cis-antisense exons were observed. CAGE-seq analysis revealed the presence of potential transcriptional start sites originated from the U-UBE3A-ATS spanning region. Our findings indicate novel aspects for the expression regulation in the PWS locus.

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Figures

Figure 1
Figure 1. Organization of the human PWS locus.
Schematic representation of human 15q11-q13 region (drawing is not to scale). Protein coding and snoRNA genes are marked as boxes and ovals, respectively. Paternally and maternally expressed genes are shown with dark or white colors, respectively. Dark bars indicate alternatively spliced exons of the paternally expressed U-UBE3-ATS transcript. Known and suggested U-UBE3-AS transcripts are shown as black and dashed arrows, respectively. Question marks depict regions with identified internal TSS-tags (see also Supplementary Figure S7). The PWS imprinting center (PWS-IC) is schematically indicated by a circle.
Figure 2
Figure 2. Assembly of the npcRNA ‘expression ruler' and its application for analysis of snoRNAs from PWS locus.
(A) RT-qPCR mean Cq values for 11 npcRNA HKRs in 20 human tissue cDNA samples. The median Cq values are shown as lines, 25 to 75 Cq percentile as boxes and the range of Cq values from 20 cDNA samples as whiskers. (B) The “Expression Ruler” applied to investigate snoRNAs from PWS-locus. (C) RT-qPCR analysis of the human PWS locus snoRNAs. Normalized expression data showing fold change values obtained in 20 different human tissues by qPCR.
Figure 3
Figure 3. Comparative expression analysis of SNORD115 and SNORD116.
Expression analysis of SNORD115 and SNORD116 among 20 different human tissues performed by: (A) RT-qPCR and (B) northern blot hybridization. (A) RT-qPCR data is represented as fold change after normalization with the geometric mean of “Expression Ruler”. (B) SCARNA5 serve as loading controls in northern blot hybridization experiments.
Figure 4
Figure 4. Expression analysis of IPW116 and IPW115 exons.
Normalized expression data of IPW116 and IPW115 exons showing fold change values obtained in 20 different human tissues by qPCR. Expression results indicate that IPW116 exons exhibit an expression pattern similar to SNORD116 (A), whereas IPW115 exons show similarity to SNORD115 expression across analyzed tissues (B).
Figure 5
Figure 5. Comparative expression analysis of UBE3A cis-antisense exons and the UBE3A mRNA.
(A) Expression profiles of IPW and UBE3A cis-antisense exons in different tissues. (B) Comparative analysis of UBE3A and UBE3A cis-antisense transcripts in 20 different human tissues.
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References

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