SNORD88B-mediated WRN nucleolar trafficking drives self-renewal in liver cancer initiating cells and hepatocarcinogenesis.

Whether small nucleolar RNAs (snoRNAs) are involved in the regulation of liver cancer stem cells (CSCs) self-renewal and serve as therapeutic targets remains largely unclear. Here we show that a functional snoRNA (SNORD88B) is robustly expressed in Hepatocellular carcinoma (HCC) tumors and liver CSCs. SNORD88B deficiency abolishes the self-renewal of liver CSCs and hepatocarcinogenesis. Mechanistically, SNORD88B anchors WRN in the nucleolus, promoting XRCC5 interacts with STK4 promoter to suppress its transcription, leading to inactivation of Hippo signaling. Moreover, low expression of STK4 and high expression of XRCC5 are positively correlated with HCC poor prognosis. Additionally, snord88b knockout suppresses mouse liver tumorigenesis. Notably, co-administration of SNORD88B antisense oligonucleotides (ASOs) with MST1 agonist adapalene (ADA) exert synergistic antitumor effects and increase overall murine survival. Our findings delineate that SNORD88B drives self-renewal of liver CSCs and accelerates HCC tumorigenesis via non-canonical mechanism, providing potential targets for liver cancer therapy by eliminating liver CSCs.

Advances in the mechanism of small nucleolar RNA and its role in DNA damage response.

Small nucleolar RNAs (snoRNAs) were previously regarded as a class of functionally conserved housekeeping genes, primarily involved in the regulation of ribosome biogenesis by ribosomal RNA (rRNA) modification. However, some of them are involved in several biological processes via complex molecular mechanisms. DNA damage response (DDR) is a conserved mechanism for maintaining genomic stability to prevent the occurrence of various human diseases. It has recently been revealed that snoRNAs are involved in DDR at multiple levels, indicating their relevant theoretical and clinical significance in this field. The present review systematically addresses four main points, including the biosynthesis and classification of snoRNAs, the mechanisms through which snoRNAs regulate target molecules, snoRNAs in the process of DDR, and the significance of snoRNA in disease diagnosis and treatment. It focuses on the potential functions of snoRNAs in DDR to help in the discovery of the roles of snoRNAs in maintaining genome stability and pathological processes.

Small non-coding RNA signatures in atrial appendages of patients with atrial fibrillation.

The development of high-throughput technologies has enhanced our understanding of small non-coding RNAs (sncRNAs) and their crucial roles in various diseases, including atrial fibrillation (AF). This study aimed to systematically delineate sncRNA profiles in AF patients. PANDORA-sequencing was used to examine the sncRNA profiles of atrial appendage tissues from AF and non-AF patients. Differentially expressed sncRNAs were identified using the R package DEGseq 2 with a fold change >2 and p < 0.05. The target genes of the differentially expressed sncRNAs were predicted using MiRanda and RNAhybrid. Gene Ontology (GO) categories and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. In AF patients, the most abundant sncRNAs were ribosomal RNA-derived small RNAs (rsRNAs), followed by transfer RNA-derived small RNAs (tsRNAs), and microRNAs (miRNAs). Compared with non-AF patients, 656 rsRNAs, 45 miRNAs, 191 tsRNAs and 51 small nucleolar RNAs (snoRNAs) were differentially expressed in AF patients, whereas no significantly differentially expressed piwi-interacting RNAs were identified. Two out of three tsRNAs were confirmed to be upregulated in AF patients by quantitative reverse transcriptase polymerase chain reaction, and higher plasma levels of tsRNA 5006c-LysCTT were associated with a 2.55-fold increased risk of all-cause death in AF patients (hazard ratio: 2.55; 95% confidence interval, 1.56-4.17; p < 0.001). Combined with our previous transcriptome sequencing results, 32 miRNA, 31 snoRNA, 110 nucleus-encoded tsRNA, and 33 mitochondria-encoded tsRNA target genes were dysregulated in AF patients. GO and KEGG analyses revealed enrichment of differentially expressed sncRNA target genes in AF-related pathways, including the 'calcium signaling pathway' and 'adrenergic signaling in cardiomyocytes.' The dysregulated sncRNA profiles in AF patients suggest their potential regulatory roles in AF pathogenesis. Further research is needed to investigate the specific mechanisms of sncRNAs in the development of AF and to explore potential biomarkers for AF treatment and prognosis.

SnoRNAs: Exploring Their Implication in Human Diseases.

Small nucleolar RNAs (snoRNAs) are earning increasing attention from research communities due to their critical role in the post-transcriptional modification of various RNAs. These snoRNAs, along with their associated proteins, are crucial in regulating the expression of a vast array of genes in different human diseases. Primarily, snoRNAs facilitate modifications such as 2'-O-methylation, N-4-acetylation, and pseudouridylation, which impact not only ribosomal RNA (rRNA) and their synthesis but also different RNAs. Functionally, snoRNAs bind with core proteins to form small nucleolar ribonucleoproteins (snoRNPs). These snoRNAs then direct the protein complex to specific sites on target RNA molecules where modifications are necessary for either standard cellular operations or the regulation of pathological mechanisms. At these targeted sites, the proteins coupled with snoRNPs perform the modification processes that are vital for controlling cellular functions. The unique characteristics of snoRNAs and their involvement in various non-metabolic and metabolic diseases highlight their potential as therapeutic targets. Moreover, the precise targeting capability of snoRNAs might be harnessed as a molecular tool to therapeutically address various disease conditions. This review delves into the role of snoRNAs in health and disease and explores the broad potential of these snoRNAs as therapeutic agents in human pathologies.

The landscape of RNA-chromatin interaction reveals small non-coding RNAs as essential mediators of leukemia maintenance.

RNA constitutes a large fraction of chromatin. Spatial distribution and functional relevance of most of RNA-chromatin interactions remain unknown. We established a landscape analysis of RNA-chromatin interactions in human acute myeloid leukemia (AML). In total more than 50 million interactions were captured in an AML cell line. Protein-coding mRNAs and long non-coding RNAs exhibited a substantial number of interactions with chromatin in cis suggesting transcriptional activity. In contrast, small nucleolar RNAs (snoRNAs) and small nuclear RNAs (snRNAs) associated with chromatin predominantly in trans suggesting chromatin specific functions. Of note, snoRNA-chromatin interaction was associated with chromatin modifications and occurred independently of the classical snoRNA-RNP complex. Two C/D box snoRNAs, namely SNORD118 and SNORD3A, displayed high frequency of trans-association with chromatin. The transcription of SNORD118 and SNORD3A was increased upon leukemia transformation and enriched in leukemia stem cells, but decreased during myeloid differentiation. Suppression of SNORD118 and SNORD3A impaired leukemia cell proliferation and colony forming capacity in AML cell lines and primary patient samples. Notably, this effect was leukemia specific with less impact on healthy CD34+ hematopoietic stem and progenitor cells. These findings highlight the functional importance of chromatin-associated RNAs overall and in particular of SNORD118 and SNORD3A in maintaining leukemia propagation.

TRIM24 Cooperates with Ras Mutation to Drive Glioma Progression through snoRNA Recruitment of PHAX and DNA-PKcs.

The factors driving glioma progression remain poorly understood. Here, the epigenetic regulator TRIM24 is identified as a driver of glioma progression, where TRIM24 overexpression promotes HRasV12 anaplastic astrocytoma (AA) progression into epithelioid GBM (Ep-GBM)-like tumors. Co-transfection of TRIM24 with HRasV12 also induces Ep-GBM-like transformation of human neural stem cells (hNSCs) with tumor protein p53 gene (TP53) knockdown. Furthermore, TRIM24 is highly expressed in clinical Ep-GBM specimens. Using single-cell RNA-sequencing (scRNA-Seq), the authors show that TRIM24 overexpression impacts both intratumoral heterogeneity and the tumor microenvironment. Mechanically, HRasV12 activates phosphorylated adaptor for RNA export (PHAX) and upregulates U3 small nucleolar RNAs (U3 snoRNAs) to recruit Ku-dependent DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Overexpressed TRIM24 is also recruited by PHAX to U3 snoRNAs, thereby facilitating DNA-PKcs phosphorylation of TRIM24 at S767/768 residues. Phosphorylated TRIM24 induces epigenome and transcription factor network reprogramming and promotes Ep-GBM-like transformation. Targeting DNA-PKcs with the small molecule inhibitor NU7441 synergizes with temozolomide to reduce Ep-GBM tumorigenicity and prolong animal survival. These findings provide new insights into the epigenetic regulation of Ep-GBM-like transformation and suggest a potential therapeutic strategy for patients with Ep-GBM.

Truncated variants of MAGEL2 are involved in the etiologies of the Schaaf-Yang and Prader-Willi syndromes.

The neurodevelopmental disorders Prader-Willi syndrome (PWS) and Schaaf-Yang syndrome (SYS) both arise from genomic alterations within human chromosome 15q11-q13. A deletion of the SNORD116 cluster, encoding small nucleolar RNAs, or frameshift mutations within MAGEL2 result in closely related phenotypes in individuals with PWS or SYS, respectively. By investigation of their subcellular localization, we observed that in contrast to a predominant cytoplasmic localization of wild-type (WT) MAGEL2, a truncated MAGEL2 mutant was evenly distributed between the cytoplasm and the nucleus. To elucidate regulatory pathways that may underlie both diseases, we identified protein interaction partners for WT or mutant MAGEL2, in particular the survival motor neuron protein (SMN), involved in spinal muscular atrophy, and the fragile-X-messenger ribonucleoprotein (FMRP), involved in autism spectrum disorders. The interactome of the non-coding RNA SNORD116 was also investigated by RNA-CoIP. We show that WT and truncated MAGEL2 were both involved in RNA metabolism, while regulation of transcription was mainly observed for WT MAGEL2. Hence, we investigated the influence of MAGEL2 mutations on the expression of genes from the PWS locus, including the SNORD116 cluster. Thereby, we provide evidence for MAGEL2 mutants decreasing the expression of SNORD116, SNORD115, and SNORD109A, as well as protein-coding genes MKRN3 and SNRPN, thus bridging the gap between PWS and SYS.

The rRNA epitranscriptome and myonuclear SNORD landscape in skeletal muscle fibers contributes to ribosome heterogeneity and is altered by a hypertrophic stimulus.

In cell biology, ribosomal RNA (rRNA) 2'O-methyl (2'-O-Me) is the most prevalent posttranscriptional chemical modification contributing to ribosome heterogeneity. The modification involves a family of small nucleolar RNAs (snoRNAs) and is specified by box C/D snoRNAs (SNORDs). Given the importance of ribosome biogenesis for skeletal muscle growth, we asked if rRNA 2'-O-Me in nascent ribosomes synthesized in response to a growth stimulus is an unrecognized mode of ribosome heterogeneity in muscle. To determine the pattern and dynamics of 2'-O-Me rRNA, we used a sequencing-based profiling method called RiboMeth-seq (RMS). We applied this method to tissue-derived rRNA of skeletal muscle and rRNA specifically from the muscle fiber using an inducible myofiber-specific RiboTag mouse in sedentary and mechanically overloaded conditions. These analyses were complemented by myonuclear-specific small RNA sequencing to profile SNORDs and link the rRNA epitranscriptome to known regulatory elements generated within the muscle fiber. We demonstrate for the first time that mechanical overload of skeletal muscle 1) induces decreased 2'-O-Me at a subset of skeletal muscle rRNA and 2) alters the SNORD profile in isolated myonuclei. These findings point to a transient diversification of the ribosome pool via 2'-O-Me during growth and adaptation in skeletal muscle. These findings suggest changes in ribosome heterogeneity at the 2'-O-Me level during muscle hypertrophy and lay the foundation for studies investigating the functional implications of these newly identified "growth-induced" ribosomes.NEW & NOTEWORTHY Ribosomal RNAs (rRNAs) are posttranscriptionally modified by 2'O-methyl (2'-O-Me). This study applied RiboMeth-seq (RMS) to detect changes in 2'-O-Me levels during skeletal muscle hypertrophy, uncovering transient diversification of the ribosome pool in skeletal muscle fibers. This work implies a role for ribosome heterogeneity in skeletal muscle growth and adaptation.

Loss of Conserved rRNA Modifications in the Peptidyl Transferase Center Leads to Diminished Protein Synthesis and Cell Growth in Budding Yeast.

Ribosomal RNAs (rRNAs) are extensively modified during the transcription and subsequent maturation. Three types of modifications, 2'-O-methylation of ribose moiety, pseudouridylation, and base modifications, are introduced either by a snoRNA-driven mechanism or by stand-alone enzymes. Modified nucleotides are clustered at the functionally important sites, including peptidyl transferase center (PTC). Therefore, it has been hypothesised that the modified nucleotides play an important role in ensuring the functionality of the ribosome. In this study, we demonstrate that seven 25S rRNA modifications, including four evolutionarily conserved modifications, in the proximity of PTC can be simultaneously depleted without loss of cell viability. Yeast mutants lacking three snoRNA genes (snR34, snR52, and snR65) and/or expressing enzymatically inactive variants of spb1(D52A/E679K) and nop2(C424A/C478A) were constructed. The results show that rRNA modifications in PTC contribute collectively to efficient translation in eukaryotic cells. The deficiency of seven modified nucleotides in 25S rRNA resulted in reduced cell growth, cold sensitivity, decreased translation levels, and hyperaccurate translation, as indicated by the reduced missense and nonsense suppression. The modification m5C2870 is crucial in the absence of the other six modified nucleotides. Thus, the pattern of rRNA-modified nucleotides around the PTC is essential for optimal ribosomal translational activity and translational fidelity.

Identification of novel snoRNA-based biomarkers for clear cell renal cell carcinoma from urine-derived extracellular vesicles.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC with high rates of metastasis. Targeted therapies such as tyrosine kinase and checkpoint inhibitors have improved treatment success, but therapy-related side effects and tumor recurrence remain a challenge. As a result, ccRCC still have a high mortality rate. Early detection before metastasis has great potential to improve outcomes, but no suitable biomarker specific for ccRCC is available so far. Therefore, molecular biomarkers derived from body fluids have been investigated over the past decade. Among them, RNAs from urine-derived extracellular vesicles (EVs) are very promising. METHODS: RNA was extracted from urine-derived EVs from a cohort of 78 subjects (54 ccRCC patients, 24 urolithiasis controls). RNA-seq was performed on the discovery cohort, a subset of the whole cohort (47 ccRCC, 16 urolithiasis). Reads were then mapped to the genome, and expression was quantified based on 100 nt long contiguous genomic regions. Cluster analysis and differential region expression analysis were performed with adjustment for age and gender. The candidate biomarkers were validated by qPCR in the entire cohort. Receiver operating characteristic, area under the curve and odds ratios were used to evaluate the diagnostic potential of the models. RESULTS: An initial cluster analysis of RNA-seq expression data showed separation by the subjects' gender, but not by tumor status. Therefore, the following analyses were done, adjusting for gender and age. The regions differentially expressed between ccRCC and urolithiasis patients mainly overlapped with small nucleolar RNAs (snoRNAs). The differential expression of four snoRNAs (SNORD99, SNORD22, SNORD26, SNORA50C) was validated by quantitative PCR. Confounder-adjusted regression models were then used to classify the validation cohort into ccRCC and tumor-free subjects. Corresponding accuracies ranged from 0.654 to 0.744. Models combining multiple genes and the risk factors obesity and hypertension showed improved diagnostic performance with an accuracy of up to 0.811 for SNORD99 and SNORA50C (p = 0.0091). CONCLUSIONS: Our study uncovered four previously unrecognized snoRNA biomarkers from urine-derived EVs, advancing the search for a robust, easy-to-use ccRCC screening method.

U3 snoRNA inter-regulates with DDX21 in the perichromosomal region to control mitosis.

U3 snoRNA is essential for ribosome biogenesis during interphase. Upon mitotic onset, the nucleolus disassembles and U3 snoRNA relocates to the perichromosomal region (PR) to be considered as a chromosome passenger. Whether U3 controls mitosis remains unknown. Here, we demonstrate that U3 snoRNA is required for mitotic progression. We identified DDX21 as the predominant U3-binding protein during mitosis and confirmed that U3 snoRNA colocalizes with DDX21 in the PR. DDX21 knockdown induces mitotic catastrophe and similar mitotic defects caused by U3 snoRNA depletion. Interestingly, the uniform PR distribution of U3 snoRNA and DDX21 is interdependent. DDX21 functions in mitosis depending on its PR localization. Mechanistically, U3 snoRNA regulates DDX21 PR localization through maintaining its mobility. Moreover, Cy5-U3 snoRNA downsizes the fibrous condensates of His-DDX21 at proper molecular ratios in vitro. This work highlights the importance of the equilibrium between U3 snoRNA and DDX21 in PR formation and reveals the potential relationship between the PR assembly and mitotic regulation.

HIV-1 Infection Reduces NAD Capping of Host Cell snRNA and snoRNA.

Nicotinamide adenine dinucleotide (NAD) is a critical component of the cellular metabolism and also serves as an alternative 5' cap on various RNAs. However, the function of the NAD RNA cap is still under investigation. We studied NAD capping of RNAs in HIV-1-infected cells because HIV-1 is responsible for the depletion of the NAD/NADH cellular pool and causing intracellular pellagra. By applying the NAD captureSeq protocol to HIV-1-infected and uninfected cells, we revealed that four snRNAs (e.g., U1) and four snoRNAs lost their NAD cap when infected with HIV-1. Here, we provide evidence that the presence of the NAD cap decreases the stability of the U1/HIV-1 pre-mRNA duplex. Additionally, we demonstrate that reducing the quantity of NAD-capped RNA by overexpressing the NAD RNA decapping enzyme DXO results in an increase in HIV-1 infectivity. This suggests that NAD capping is unfavorable for HIV-1 and plays a role in its infectivity.

Role of small nucleolar RNAs in alternative splicing of the doublesex gene in the silkworm, Bombyx mori.

More and more evidence shows that small noncoding RNAs (ncRNAs) play diverse roles in development, stress response and other cellular processes, but functional study of intermediate-size ncRNAs is still rare. Here, the expression profile of 16 intermediate-size ncRNAs in ovary and testis of silkworm Bombyx mori were analyzed. Twelve ncRNAs, including 5 small nucleolar RNAs (snoRNAs) and 7 unclassified ncRNAs, accumulated more in the testis than in the ovary of silkworm, especially Bm-163, Bm-51 and Bm-68. Four ncRNAs (including three orphan snoRNAs and one unclassified ncRNA) had higher expression level in the ovary than in the testis, especially Bm-86. Overexpression of the testis-enriched snoRNA Bm-68 in the female led to the accumulation of male-specific isoform of doublesex (BmdsxM) and increased the expression ratio of BmdsxM: BmdsxF. While overexpression of ovary-enriched snoRNA Bm-86 in the male decreased the expression ratio of BmdsxM: BmdsxF, indicating the roles of the two snoRNAs played in the alternative splicing of Bmdsx of silkworm, which will provide new clues for the functional study of snoRNAs in insects.

Small Nucleolar RNAs as Diagnostic and Prognostic Biomarkers in Cancer: A Systematic Review and Meta-Analysis.

OBJECTIVES: Small nucleolar RNAs (snoRNAs) form clusters within the genome, representing a mysterious category of small non-coding RNAs. Research has demonstrated that aberrant snoRNAs can contribute to the development of various types of cancers. Recent studies have identified snoRNAs as potentially valuable biomarkers for the diagnosis or/and prognosis of cancers. However, there has been a lack of comprehensive reviews on prognostic and diagnostic snoRNAs across different types of cancers. METHODS: We conducted a systematic search of various databases including Google Scholar, Medline, Cochrane, Scopus, PubMed, Embase, ScienceDirect, Ovid-Medline, Chinese National Knowledge Infrastructure, WanFang, and SinoMed with a time frame reception to December 30, 2022. A total of 49 relevant articles were included in our analysis, consisting of 21 articles focusing on diagnostic aspects and 41 articles focusing on prognostic aspects. Pooled odds ratio, 95% confidence intervals (CIs), and hazard ratio (HR) were utilized to evaluate clinical parameters and overall survival (OS), respectively. RESULT: The findings indicated that area under the curve, sensitivity, and specificity were 0.85, 75%, and 80% in cancer, respectively. There was a possibility that snoRNAs had a positive impact on the diagnosis (risk ratio, RR = 2.95, 95% CI: 2.75-3.16, P = 0.000) and OS (HR = 1) in cancer. Additionally, abnormally expressed snoRNAs were associated with a positive impact on OS time for chronic lymphocytic leukemia (HR: 0.88, 95%Cl: 0.69-1.11, P < 0.00001), colon adenocarcinoma (HR: 0.97, 95%Cl: 0.91-1.03, P < 0.0001), and ovarian cancer (HR: 0.98, 95%Cl: 0.98-0.99, P < 0.00001). However, dysregulated snoRNAs of colon cancer and colorectal cancer had a negative impact on OS time (HR = 3.01 and 1.01 respectively, P < 0.0001). CONCLUSION: The results strongly suggested that snoRNAs could serve as potential novel indicators for prognosis and diagnosis in cancers. This systematic review followed the guidelines of the Transparent Reporting of Systematic Review and Meta-Analyses (PROSPERO register: CRD42020209096).

The Transcriptional Landscape of Coding and Noncoding RNAs in Recurrent and Nonrecurrent Colon Cancer.

A number of patients with colon cancer with local or local advanced disease suffer from recurrence and there is an urgent need for better prognostic biomarkers in this setting. Here, the transcriptomic landscape of mRNAs, long noncoding RNAs, snRNAs, small nucleolar RNAs (snoRNAs), small Cajal body-specific RNAs, pseudogenes, and circular RNAs, as well as RNAs denoted as miscellaneous RNAs, was profiled by total RNA sequencing. In addition to well-known coding and noncoding RNAs, differential expression analysis also uncovered transcripts that have not been implicated previously in colon cancer, such as RNA5SP149, RNU4-2, and SNORD3A. Moreover, there was a profound global up-regulation of snRNA pseudogenes, snoRNAs, and rRNA pseudogenes in more advanced tumors. A global down-regulation of circular RNAs in tumors relative to normal tissues was observed, although only a few were expressed differentially between tumor stages. Many previously undescribed transcripts, including RNU6-620P, RNU2-20P, VTRNA1-3, and RNA5SP60, indicated strong prognostic biomarker potential in receiver operating characteristics analyses. In summary, this study unveiled numerous differentially expressed RNAs across various classes between recurrent and nonrecurrent colon cancer. Notably, there was a significant global up-regulation of snRNA pseudogenes, snoRNAs, and rRNA pseudogenes in advanced tumors. Many of these newly discovered candidates demonstrate a strong prognostic potential for stage II colon cancer.

HMGB1 prefers to interact with structural RNAs and regulates rRNA methylation modification and translation in HeLa cells.

BACKGROUND: High-mobility group B1 (HMGB1) is both a DNA binding nuclear factor modulating transcription and a crucial cytokine that mediates the response to both infectious and noninfectious inflammation such as autoimmunity, cancer, trauma, and ischemia reperfusion injury. HMGB1 has been proposed to control ribosome biogenesis, similar as the other members of a class of HMGB proteins. RESULTS: Here, we report that HMGB1 selectively promotes transcription of genes involved in the regulation of transcription, osteoclast differentiation and apoptotic process. Improved RNA immunoprecipitation by UV cross-linking and deep sequencing (iRIP-seq) experiment revealed that HMGB1 selectively bound to mRNAs functioning not only in signal transduction and gene expression, but also in axon guidance, focal adhesion, and extracellular matrix organization. Importantly, HMGB1-bound reads were strongly enriched in specific structured RNAs, including the domain II of 28S rRNA, H/ACA box snoRNAs including snoRNA63 and scaRNAs. RTL-P experiment showed that overexpression of HMGB1 led to a decreased methylation modification of 28S rRNA at position Am2388, Cm2409, and Gm2411. We further showed that HMGB1 overexpression increased ribosome RNA expression levels and enhanced protein synthesis. CONCLUSION: Taken together, our results support a model in which HMGB1 binds to multiple RNA species in human cancer cells, which could at least partially contribute to HMGB1-modulated rRNA modification, protein synthesis function of ribosomes, and differential gene expression including rRNA genes. These findings provide additional mechanistic clues to HMGB1 functions in cancers and cell differentiation.

IGCNSDA: unraveling disease-associated snoRNAs with an interpretable graph convolutional network.

Accurately delineating the connection between short nucleolar RNA (snoRNA) and disease is crucial for advancing disease detection and treatment. While traditional biological experimental methods are effective, they are labor-intensive, costly and lack scalability. With the ongoing progress in computer technology, an increasing number of deep learning techniques are being employed to predict snoRNA-disease associations. Nevertheless, the majority of these methods are black-box models, lacking interpretability and the capability to elucidate the snoRNA-disease association mechanism. In this study, we introduce IGCNSDA, an innovative and interpretable graph convolutional network (GCN) approach tailored for the efficient inference of snoRNA-disease associations. IGCNSDA leverages the GCN framework to extract node feature representations of snoRNAs and diseases from the bipartite snoRNA-disease graph. SnoRNAs with high similarity are more likely to be linked to analogous diseases, and vice versa. To facilitate this process, we introduce a subgraph generation algorithm that effectively groups similar snoRNAs and their associated diseases into cohesive subgraphs. Subsequently, we aggregate information from neighboring nodes within these subgraphs, iteratively updating the embeddings of snoRNAs and diseases. The experimental results demonstrate that IGCNSDA outperforms the most recent, highly relevant methods. Additionally, our interpretability analysis provides compelling evidence that IGCNSDA adeptly captures the underlying similarity between snoRNAs and diseases, thus affording researchers enhanced insights into the snoRNA-disease association mechanism. Furthermore, we present illustrative case studies that demonstrate the utility of IGCNSDA as a valuable tool for efficiently predicting potential snoRNA-disease associations. The dataset and source code for IGCNSDA are openly accessible at: https://github.com/altriavin/IGCNSDA.

Small Non-Coding RNAs and Their Role in Locoregional Metastasis and Outcomes in Early-Stage Breast Cancer Patients.

Deregulation of small non-coding RNAs (sncRNAs) has been associated with the onset of metastasis. We evaluated the expression of sncRNAs in patients with early-stage breast cancer, performing RNA sequencing in 60 patients for whom tumor and sentinel lymph node (SLN) samples were available, and conducting differential expression, gene ontology, enrichment and survival analyses. Sequencing annotation classified most of the sncRNAs into small nucleolar RNA (snoRNAs, 70%) and small nuclear RNA (snRNA, 13%). Our results showed no significant differences in sncRNA expression between tumor or SLNs obtained from the same patient. Differential expression analysis showed down-regulation (n = 21) sncRNAs and up-regulation (n = 2) sncRNAs in patients with locoregional metastasis. The expression of SNHG5, SNORD90, SCARNA2 and SNORD78 differentiated luminal A from luminal B tumors, whereas SNORD124 up-regulation was associated with luminal B HER2+ tumors. Discriminating analysis and receiver-operating curve analysis revealed a signature of six snoRNAs (SNORD93, SNORA16A, SNORD113-6, SNORA7A, SNORA57 and SNORA18A) that distinguished patients with locoregional metastasis and predicted patient outcome. Gene ontology and Reactome pathway analysis showed an enrichment of biological processes associated with translation initiation, protein targeting to specific cell locations, and positive regulation of Wnt and NOTCH signaling pathways, commonly involved in the promotion of metastases. Our results point to the potential of several sncRNAs as surrogate markers of lymph node metastases and patient outcome in early-stage breast cancer patients. Further preclinical and clinical studies are required to understand the biological significance of the most significant sncRNAs and to validate our results in a larger cohort of patients.

SNORA69 is up-regulated in the lateral habenula of individuals with major depressive disorder.

Major depressive disorder (MDD) is a complex and potentially debilitating illness whose etiology and pathology remains unclear. Non-coding RNAs have been implicated in MDD, where they display differential expression in the brain and the periphery. In this study, we quantified small nucleolar RNA (snoRNA) expression by small RNA sequencing in the lateral habenula (LHb) of individuals with MDD (n = 15) and psychiatrically-healthy controls (n = 15). We uncovered five snoRNAs that exhibited differential expression between MDD and controls (FDR < 0.01). Specifically, SNORA69 showed increased expression in MDD and was technically validated via RT-qPCR. We further investigated the expression of Snora69 in the LHb and peripheral blood of an unpredicted chronic mild stress (UCMS) mouse model of depression. Snora69 was specifically up-regulated in mice that underwent the UCMS paradigm. SNORA69 is known to guide pseudouridylation onto 5.8S and 18S rRNAs. We quantified the relative abundance of pseudouridines on 5.8S and 18S rRNA in human post-mortem LHb samples and found increased abundance of pseudouridines in the MDD group. Overall, our findings indicate the importance of brain snoRNAs in the pathology of MDD. Future studies characterizing SNORA69's role in MDD pathology is warranted.

The regulatory roles of small nucleolar RNAs within their host locus.

Small nucleolar RNAs (snoRNAs) are a class of conserved noncoding RNAs forming complexes with proteins to catalyse site-specific modifications on ribosomal RNA. Besides this canonical role, several snoRNAs are now known to regulate diverse levels of gene expression. While these functions are carried out in trans by mature snoRNAs, evidence has also been emerging of regulatory roles of snoRNAs in cis, either within their genomic locus or as longer transcription intermediates during their maturation. Herein, we review recent findings that snoRNAs can interact in cis with their intron to regulate the expression of their host gene. We also explore the ever-growing diversity of longer host-derived snoRNA extensions and their functional impact across the transcriptome. Finally, we discuss the role of snoRNA duplications into forging these new layers of snoRNA-mediated regulation, as well as their involvement in the genomic imprinting of their host locus.