Eukaryotic snoRNAs: A paradigm for gene expression flexibility

Dieci, Giorgio; Preti, Milena; Montanini, Barbara

doi:10.1016/j.ygeno.2009.05.002

Cited by 285 publications

(296 citation statements)

References 77 publications

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“…After splicing, exonucleolytic processing of the debranched lariat generates mature snoRNAs with 5′-monophosphates, at least in those snoRNAs tested (32). Other snoRNAs are independent genes that are transcribed by RNA polymerase (pol) II and thus have a 5′-cap (33). According to the current mouse genome annotation from the University of California at Santa Cruz (UCSC) Genome Browser (December 2011, GRCm38/mm10), SNORA3 and SNORA71 are encoded in the introns of RPl27a and of a noncoding RNA, respectively.…”

Section: Discussionmentioning

confidence: 99%

Potential role for snoRNAs in PKR activation during metabolic stress

Youssef

Safran

Nakamura

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

100

103

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Protein kinase RNA-activated (PKR) has long been known to be activated by viral double-stranded RNA (dsRNA) as part of the mammalian immune response. However, in mice PKR is also activated by metabolic stress in the absence of viral infection, and this requires a functional kinase domain, as well as a functional dsRNA-binding domain. The endogenous cellular RNA that potentially leads to PKR activation during metabolic stress is unknown. We investigated this question using mouse embryonic fibroblast cells expressing wild-type PKR (PKR WT ) or PKR with a point mutation in each dsRNA-binding motif (PKR RM ). Using this system, we identified endogenous RNA that interacts with PKR after induction of metabolic stress by palmitic acid (PA) treatment. Specifically, RIP-Seq analyses showed that the majority of enriched RNAs that interacted with WT PKR (≥twofold, false discovery rate ≤ 5%) were small nucleolar RNAs (snoRNAs). Immunoprecipitation of PKR in extracts of UV-cross-linked cells, followed by RT-qPCR, confirmed that snoRNAs were enriched in PKR WT samples after PA treatment, but not in the PKR RM samples. We also demonstrated that a subset of identified snoRNAs bind and activate PKR in vitro; the presence of a 5′-triphosphate enhanced PKR activity compared with the activity with a 5′-monophosphate, for some, but not all, snoRNAs. Finally, we demonstrated PKR activation in cells upon snoRNA transfection, supporting our hypothesis that endogenous snoRNAs can activate PKR. Our results suggest an unprecedented and unexpected model whereby snoRNAs play a role in the activation of PKR under metabolic stress.PKR | snoRNA | metabolic stress | phosphorylation | RNA-binding protein

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Section: Discussionmentioning

confidence: 99%

Potential role for snoRNAs in PKR activation during metabolic stress

Youssef

Safran

Nakamura

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

100

103

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“…Small nucleolar RNAs (snoRNAs) are 60-300 nucleotide-long ncRNAs that are excised from the intron regions of pre-mRNAs, usually those encoding fundamental housekeeping proteins. [3][4][5] There are two structurally distinct classes of snoRNAs, called the box C/D and H/ACA snoRNAs, which function mainly as guide RNAs in the site-specific 2 0 -O-methylation and pseudouridylation of rRNAs, respectively. 3,6,7 However, a subgroup of so-called 'orphan' snoRNAs exists that lacks any apparent complementarity to cellular RNAs and therefore has unknown function.…”

Section: Introductionmentioning

confidence: 99%

Specific small nucleolar RNA expression profiles in acute leukemia

et al. 2012

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Apart from microRNAs, little is known about the regulation of expression of non-coding RNAs in cancer. We investigated whether small nucleolar RNAs (snoRNAs) accumulation displayed specific signatures in acute myeloblastic and acute lymphoblastic leukemias. Using microarrays and high-throughput quantitative PCR (qPCR), we demonstrate here that snoRNA expression patterns are negatively altered in leukemic cells compared with controls. Interestingly, a specific signature was found in acute promyelocytic leukemia (APL) with ectopic expression of SNORD112-114 snoRNAs located at the DLK1-DIO3 locus. In vitro experiments carried out on APL blasts demonstrate that transcription of these snoRNAs was lost under all-trans retinoic acid-mediated differentiation and induced by enforced expression of the PML-RARalpha fusion protein in negative leukemic cell lines. Further experiments revealed that the SNORD114-1 (14q(II-1)) variant promoted cell growth through cell cycle modulation; its expression was implicated in the G0/G1 to S phase transition mediated by the Rb/p16 pathways. This study thus reports three important observations: (1) snoRNA regulation is different in normal cells compared with cancer cells; (2) a relationship exists between a chromosomal translocation and expression of snoRNA loci; and (3) snoRNA expression can affect Rb/p16 cell cycle regulation. Taken together, these data strongly suggest that snoRNAs have a role in cancer development.

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“…SNORD5 is a C/D box type of snoRNA expressed in several tissues (28) and although it is primarily associated with methylation, these RNAs have also demonstrated gene expression flexibility (29). However, its reported function of methylation is interesting in the current context, as it suggests that this may be one of the mechanisms that explains the epigenetic actions of testosterone described in previous reports (30,31).…”

Section: Figurementioning

confidence: 88%

Androgen-responsive non-coding small RNAs extend the potential of HCG stimulation to act as a bioassay of androgen sufficiency

Rodie

Mudaliar²,

Herzyk

et al. 2017

European Journal of Endocrinology

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Background: It is unclear whether a short-term change in circulating androgens is associated with changes in the transcriptome of the peripheral blood mononuclear cells (PBMC). Aims and methods:To explore the effect of hCG stimulation on the PBMC transcriptome, 12 boys with a median age (range) of 0.7 years (0.3, 11.2) who received intramuscular hCG 1500u on 3 consecutive days as part of their investigations underwent transcriptomic array analysis on RNA extracted from peripheral blood mononuclear cells before and after hCG stimulation. Results: Median pre-and post-hCG testosterone for the overall group was 0.7 nmol/L (<0.5, 6) and 7.9 nmol/L (<0.5, 31.5), respectively. Of the 12 boys, 3 (25%) did not respond to hCG stimulation with a pre and post median serum testosterone of <0.5 nmol/L and <0.5 nmol/L, respectively. When corrected for gene expression changes in the nonresponders to exclude hCG effects, all 9 of the hCG responders consistently demonstrated a 20% or greater increase in the expression of piR-37153 and piR-39248, non-coding PIWI-interacting RNAs (piRNAs). In addition, of the 9 responders, 8, 6 and 4 demonstrated a 30, 40 and 50% rise, respectively, in a total of 2 further piRNAs. In addition, 3 of the responders showed a 50% or greater rise in the expression of another small RNA, SNORD5. On comparing fold-change in serum testosterone with fold-change in the above transcripts, a positive correlation was detected for SNORD5 (P = 0.01). Conclusions: The identification of a dynamic and androgen-responsive PBMC transcriptome extends the potential value of the hCG test for the assessment of androgen sufficiency.

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Eukaryotic snoRNAs: A paradigm for gene expression flexibility

Cited by 285 publications

References 77 publications

Potential role for snoRNAs in PKR activation during metabolic stress

Potential role for snoRNAs in PKR activation during metabolic stress

Specific small nucleolar RNA expression profiles in acute leukemia

Androgen-responsive non-coding small RNAs extend the potential of HCG stimulation to act as a bioassay of androgen sufficiency

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