01-P010 Prader–Willi Syndrome and small nucleolar RNAs

Small nucleolar RNAs (snoRNAs) are molecules placed in the cell nucleolus and in Cajal bodies. Many scientific reports clearly show that snoRNAs are not only responsible for modifications of other RNAs but also possess multiple other functions such as metabolic stress regulation or modulation of alternative splicing. Full-length snoRNAs as well as small RNAs derived from snoRNAs have been implied in human diseases such as cancer or Prader – Willi Syndrome. In this review we would like to describe these non – canonical roles of snoRNAs and their derivatives with the emphasis on their role in human diseases.

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Evidence for the Role of PWCR1/HBII-85 C/D Box Small Nucleolar RNAs in Prader-Willi Syndrome

The American Journal of Human Genetics ◽

10.1086/342408 ◽

2002 ◽

Vol 71 (3) ◽

pp. 669-678 ◽

Cited By ~ 87

Author(s):

Renata C. Gallagher ◽

Birgit Pils ◽

Mohammed Albalwi ◽

Uta Francke

Keyword(s):

Prader Willi Syndrome ◽

Small Nucleolar Rnas ◽

Nucleolar Rnas

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Natural copy number differences of tandemly repeated small nucleolar RNAs in the Prader-Willi syndrome genomic region regulate individual behavioral responses in mammals

10.1101/476010 ◽

2018 ◽

Cited By ~ 1

Author(s):

Maryam Keshavarz ◽

Rebecca Krebs-Wheaton ◽

Peter Refki ◽

Yoland Savriama ◽

Yi Zhang ◽

...

Keyword(s):

Gaba Receptors ◽

Copy Number ◽

Serotonin Receptor ◽

Target Genes ◽

Phenotypic Variability ◽

Inbred Mouse Strain ◽

Prader Willi Syndrome ◽

Small Nucleolar Rnas ◽

Copy Numbers ◽

Nucleolar Rnas

AbstractThe Prader-Willi Syndrome (PWS) gene region is an imprinted gene complex involved in behavioral, metabolic and osteogenic functions. We have analyzed here the variation of two families of regulatory small nucleolar RNAs (SNORD115 and SNORD116) that are coded within the PWS and are expressed from the paternal chromosome. They are organized in two tandemly repeated clusters which are naturally copy number variable between individuals. We find that the copy numbers at these loci correlate with repeatable individual test scores for anxiety that are considered to constitute a component of the “personality” of individuals. We show this for different populations and species of mice, cavies and for the anxiety component of personality tests in humans. This is also the case for an inbred mouse strain (C57Bl6) implying that copy number variation creates phenotypic variability even in an isogenic background. In transcriptome data from brain samples of this strain we find SNORD copy-number correlated regulation of target genes that are known to be involved in influencing behavior. SNORD115 has previously been suggested to regulate splicing of the serotonin receptor Htr2c and we confirm this in our data. For SNORD116 we provide evidence that it regulates the expression level of the chromatin regulator Ankrd11, which itself regulates GABA receptors, metabolic pathways, cell differentiation and osteogenesis. Intriguingly, we find that craniofacial shapes in mice correlate also with SNORD116 copy numbers. New copy number variants are generated at very high rates in mice, possibly at every generation, explaining why conventional genetic mapping could not detect this association. Our results suggest that the variable dosage of two regulatory RNAs are major determinants of individual behavioral differences and correlated traits in mammals.

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Expression of small nucleolar RNAs (D32A, D33, D35) associated with ageing and osteoarthritis in man and horses

10.26226/morressier.5ebd45acffea6f735881b050 ◽

2020 ◽

Author(s):

Mandy Peffers

Keyword(s):

Small Nucleolar Rnas ◽

Nucleolar Rnas

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Emerging Data on the Diversity of Molecular Mechanisms Involving C/D snoRNAs

Non-Coding RNA ◽

10.3390/ncrna7020030 ◽

2021 ◽

Vol 7 (2) ◽

pp. 30

Author(s):

Laeya Baldini ◽

Bruno Charpentier ◽

Stéphane Labialle

Keyword(s):

Ribosomal Rna ◽

Molecular Mechanisms ◽

Molecular Level ◽

Accurate Description ◽

Small Nucleolar Rnas ◽

Age Of Maturity ◽

Non Coding Rnas ◽

And Function ◽

Nucleolar Rnas

Box C/D small nucleolar RNAs (C/D snoRNAs) represent an ancient family of small non-coding RNAs that are classically viewed as housekeeping guides for the 2′-O-methylation of ribosomal RNA in Archaea and Eukaryotes. However, an extensive set of studies now argues that they are involved in mechanisms that go well beyond this function. Here, we present these pieces of evidence in light of the current comprehension of the molecular mechanisms that control C/D snoRNA expression and function. From this inventory emerges that an accurate description of these activities at a molecular level is required to let the snoRNA field enter in a second age of maturity.

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Site-Specific Pseudouridine Formation in Preribosomal RNA Is Guided by Small Nucleolar RNAs

Cell ◽

10.1016/s0092-8674(00)80263-9 ◽

1997 ◽

Vol 89 (5) ◽

pp. 799-809 ◽

Cited By ~ 342

Author(s):

Philippe Ganot ◽

Marie-Line Bortolin ◽

Tamás Kiss

Keyword(s):

Small Nucleolar Rnas ◽

Site Specific ◽

Nucleolar Rnas

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Three new small nucleolar RNAs that are psoralen cross-linked in vivo to unique regions of pre-rRNA

Molecular and Cellular Biology ◽

10.1128/mcb.13.7.4382-4390.1993 ◽

1993 ◽

Vol 13 (7) ◽

pp. 4382-4390

Author(s):

O J Rimoldi ◽

B Raghu ◽

M K Nag ◽

G L Eliceiri

Keyword(s):

Small Rnas ◽

18S Rrna ◽

Rnase H ◽

Antisense Oligodeoxynucleotide ◽

28S Rrna ◽

Small Nucleolar Rnas ◽

Rrna Sequence ◽

Nucleolar Rna ◽

Nucleolar Rnas

We have recently described three novel human small nucleolar RNA species with unique nucleotide sequences, which were named E1, E2, and E3. The present article describes specific psoralen photocross-linking in whole HeLa cells of E1, E2, and E3 RNAs to nucleolar pre-rRNA. These small RNAs were cross-linked to different sections of pre-rRNA. E1 RNA was cross-linked to two segments of nucleolar pre-rRNA; one was within residues 697 to 1163 of the 5' external transcribed spacer, and the other one was between nucleotides 664 and 1021 of the 18S rRNA sequence. E2 RNA was cross-linked to a region within residues 3282 to 3667 of the 28S rRNA sequence. E3 RNA was cross-linked to a sequence between positions 1021 and 1639 of the 18S rRNA sequence. Primer extension analysis located psoralen adducts in E1, E2, and E3 RNAs that were enriched in high-molecular-weight fractions of nucleolar RNA. Some of these psoralen adducts might be cross-links of E1, E2, and E3 RNAs to large nucleolar RNA. Antisense oligodeoxynucleotide-targeted RNase H digestion of nucleolar extracts revealed accessible segments in these three small RNAs. The accessible regions were within nucleotide positions 106 to 130 of E1 RNA, positions 24 to 48 and 42 to 66 of E2 RNA, and positions 7 to 16 and about 116 to 122 of E3 RNA. Some of the molecules of these small nucleolar RNAs sedimented as if associated with larger structures when both nondenatured RNA and a nucleolar extract were analyzed.

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Abstract 15984: Rpl13a Small Nucleolar RNAs Promote Oxidative Stress and Atherosclerosis

Circulation ◽

10.1161/circ.142.suppl_3.15984 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Lisheng Zhang ◽

Jiaohui Wu ◽

Andrew J Vista ◽

Leigh Brian ◽

Yushi Bai ◽

...

Keyword(s):

Oxidative Stress ◽

Carotid Arteries ◽

Neointimal Hyperplasia ◽

Foam Cells ◽

Slice Thickness ◽

Small Nucleolar Rnas ◽

And Migration ◽

Nucleolar Rnas ◽

Proliferation And Migration

Reactive oxygen species (ROS) contribute to atherogenesis. An unusual mechanism that increases cellular ROS levels and oxidative stress involves 4 ubiquitously expressed noncoding small nucleolar RNAs (snoRNAs) from introns of the ribosomal protein L13a ( Rpl13a ) locus: U32a , U33 , U34 , and U35a . We tested the hypothesis that these snoRNAs promote aortic smooth muscle cell (SMC) activation and vascular inflammation, by using “snoKO” mice with targeted deletion of the 4 snoRNAs (but not Rpl13a ). Compared with congenic WT SMCs, snoKO SMCs showed 40±20% lower ROS levels, assessed by DCF fluorescence ( p <0.02). Congruently, ROS levels were 35±5% lower in snoKO than WT aorta and carotid frozen sections ( p <0.01), assessed by CellROX Orange fluorescence. Proliferation and migration evoked by FBS and PDGF-BB, respectively, were each 30±10% less in snoKO than WT SMCs ( p <0.01 for each). To assess SMC migration and proliferation in vivo, we performed carotid artery endothelial denudation. Before injury, snoKO and WT carotid arteries were morphologically equivalent. Four wk after injury, carotid neointimal hyperplasia was 57±9% less and luminal area was 40±20 % more in snoKO than in WT mice ( p <0.01). WT and snoKO mice had equivalent heart rates and systolic blood pressures by tail-cuff plethysmography: 480±20 vs 420±80 beats/min; 133±5, 132±7 mm Hg, respectively (n=5/group). To test whether snoRNAs affect atherosclerosis, we orthotopically transplanted carotid arteries from WT and snoKO mice into congenic Apoe -/- mice. Six wk post-op, atherosclerotic neointima was 70±10% smaller in snoKO than in WT carotids ( p <0.01). To assess SMC-to-foam-cell transdifferentiation, which is ROS-dependent, carotid cross-sections were stained for apoE to identify graft-derived cells and for cholesteryl ester with BODIPY. BODIPY + foam cells comprised 21±3% and 11±7% of neointimal area in WT and snoKO carotids, respectively ( p <0.05). Confocal co-localization of apoE and BODIPY (optical slice thickness 1 μm) showed that graft-derived foam cells were 2.0±0.6-fold more prevalent in WT than in snoKO carotids ( p <0.01). We conclude that Rpl13a snoRNAs promote SMC ROS levels, proliferation and migration in vitro and in vivo, and that these snoRNAs augment atherosclerosis.

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Knock-Down of a Novel snoRNA in Tetrahymena Reveals a Dual Role in 5.8S rRNA Processing and Generation of a 26S rRNA Fragment

Biomolecules ◽

10.3390/biom8040128 ◽

2018 ◽

Vol 8 (4) ◽

pp. 128

Author(s):

Kasper Andersen ◽

Henrik Nielsen

Keyword(s):

Small Nucleolar Rnas ◽

Rrna Processing ◽

Specific Chemical ◽

Knock Down ◽

5.8S Rrna ◽

Rrna Species ◽

26S Rrna ◽

Precursor Molecules ◽

Nucleolar Rnas ◽

Function Sequence

In eukaryotes, 18S, 5.8S, and 28S rRNAs are transcribed as precursor molecules that undergo extensive modification and nucleolytic processing to form the mature rRNA species. Central in the process are the small nucleolar RNAs (snoRNAs). The majority of snoRNAs guide site specific chemical modifications but a few are involved in defining pre-rRNA cleavages. Here, we describe an unusual snoRNA (TtnuCD32) belonging to the box C/D subgroup from the ciliate Tetrahymena thermophila. We show that TtnuCD32 is unlikely to function as a modification guide snoRNA and that it is critical for cell viability. Cell lines with genetic knock-down of TtnuCD32 were impaired in growth and displayed two novel and apparently unrelated phenotypes. The most prominent phenotype is the accumulation of processing intermediates of 5.8S rRNA. The second phenotype is the decrease in abundance of a ~100 nt 26S rRNA fragment of unknown function. Sequence analysis demonstrated that TtnuCD32 share features with the essential snoRNA U14 but an alternative candidate (TtnuCD25) was more closely related to other U14 sequences. This, together with the fact that the observed rRNA processing phenotypes were not similar to what has been observed in U14 depleted cells, suggests that TtnuCD32 is a U14 homolog that has gained novel functions.

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