The Alazami Syndrome-Associated Protein LARP7 Guides U6 Small Nuclear RNA Modification and Contributes to Splicing Robustness.

The La-related protein 7 (LARP7) forms a complex with the nuclear 7SK RNA to regulate RNA polymerase II transcription. It has been implicated in cancer and the Alazami syndrome, a severe developmental disorder. Here, we report a so far unknown role of this protein in RNA modification. We show that LARP7 physically connects the spliceosomal U6 small nuclear RNA (snRNA) with a distinct subset of box C/D small nucleolar RNAs (snoRNAs) guiding U6 2'-O-methylation. Consistently, these modifications are severely compromised in the absence of LARP7. Although general splicing remains largely unaffected, transcriptome-wide analysis revealed perturbations in alternative splicing in LARP7-depleted cells. Importantly, we identified defects in 2'-O-methylation of the U6 snRNA in Alazami syndrome siblings carrying a LARP7 mutation. Our data identify LARP7 as a bridging factor for snoRNA-guided modification of the U6 snRNA and suggest that alterations in splicing fidelity contribute to the etiology of the Alazami syndrome.

Activation of PARP-1 by snoRNAs Controls Ribosome Biogenesis and Cell Growth via the RNA Helicase DDX21.

PARP inhibitors (PARPi) prevent cancer cell growth by inducing synthetic lethality with DNA repair defects (e.g., in BRCA1/2 mutant cells). We have identified an alternative pathway for PARPi-mediated growth control in BRCA1/2-intact breast cancer cells involving rDNA transcription and ribosome biogenesis. PARP-1 binds to snoRNAs, which stimulate PARP-1 catalytic activity in the nucleolus independent of DNA damage. Activated PARP-1 ADP-ribosylates DDX21, an RNA helicase that localizes to nucleoli and promotes rDNA transcription when ADP-ribosylated. Treatment with PARPi or mutation of the ADP-ribosylation sites reduces DDX21 nucleolar localization, rDNA transcription, ribosome biogenesis, protein translation, and cell growth. The salient features of this pathway are evident in xenografts in mice and human breast cancer patient samples. Elevated levels of PARP-1 and nucleolar DDX21 are associated with cancer-related outcomes. Our studies provide a mechanistic rationale for efficacy of PARPi in cancer cells lacking defects in DNA repair whose growth is inhibited by PARPi.

Noncoding snoRNA host genes are a distinct subclass of long noncoding RNAs.

Mammalian genomes are pervasively transcribed into different noncoding (nc)RNA classes, each one with its own hallmarks and exceptions. Some of them are nested into each other, such as host genes for small nucleolar RNAs (snoRNAs), which were long believed to simply act as molecular containers strictly facilitating snoRNA biogenesis. However, recent findings show that noncoding snoRNA host genes (ncSNHGs) display features different from those of 'regular' long ncRNAs (lncRNAs) and, more importantly, they can exert independent and unrelated functions to those of the encoded snoRNAs. Here, we review and summarize past and recent evidence that ncSNHGs form a defined subclass among the plethora of lncRNAs, and discuss future research that can further elucidate their biological relevance.

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.

Identification of four snoRNAs (SNORD16, SNORA73B, SCARNA4, and SNORD49B) as novel non-invasive biomarkers for diagnosis of breast cancer.

BACKGROUND: Emerging data point to the critical role of snoRNA in the emergence of different types of cancer, but scarcely in breast cancer (BC). This study aimed to clarify the differential expressions and potential diagnostic value of SNORD16, SNORA73B, SCARNA4, and SNORD49B in BC. METHODS: We screened differential snoRNAs in BC tissues and adjacent tissues through SNORic datasets, and then we further verified them in the plasma of BC patients and healthy volunteers by quantitative polymerase chain reaction (qPCR). RESULTS: These four snoRNAs: SNORD16, SNORA73B, SCARNA4, and SNORD49B were considerably more abundant in cancerous tissues than in neighboring tissues in the TCGA database. Their plasma levels were also higher in BC and early-stage BC patients when compared to healthy controls. Furthermore, the ROC curve demonstrated that BC (AUC = 0.7521) and early-stage BC (AUC = 0.7305) might be successfully distinguished from healthy people by SNORD16, SNORA73B, SCARNA4, and SNORD49B. CONCLUSION: Plasma snoRNAs: SNORD16, SNORA73B, SCARNA4, and SNORD49B were upregulated in BC and early-stage BC and can be used as potential diagnostic markers for BC and early-stage BC.

TEP SNORD12B, SNORA63, and SNORD14E as novel biomarkers for hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC).

PURPOSE: The alterations of RNA profile in tumor-educated platelets (TEPs) have been described as a novel biosource for cancer diagnostics. This study aimed to explore the potential snoRNAs in TEP as biomarkers for diagnostics of hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC). METHODS: Platelets were isolated using low-speed centrifugation and subjected to a quantitative polymerase chain reaction (qPCR) for snoRNAs detection. RESULTS: Down-regulated SNORD12B and SNORD14E as well as up-regulated SNORA63 were identified in TEP from HBV-related HCC, which could act as diagnostic biomarkers for HBV-related HCC as well as the early disease. Besides, TEP SNORD12B, SNORD14E, and SNORA63 facilitate the diagnostic performance of AFP and achieve favorable diagnostics efficiency for HBV-related HCC when combined with platelet parameters. CONCLUSIONS: Aberrant expression of SNORD12B, SNORA63, and SNORD14E in TEPs could serve as the novel and non-invasive biomarkers for HBV-related HCC diagnosis.

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.

Exploration of Giardia small nucleolar RNAs (snoRNAs) and their possible microRNA derivatives.

Small nucleolar RNAs (snoRNAs) are short non-coding RNAs that are abundant in the nucleoli of eukaryotic cells and play a crucial role in various aspects of ribosomal RNA (rRNA) maturation, including modifications such as 2'-O-methylation or pseudouridylation. On the other hand, Giardia duodenalis is a microaerophilic, flagellated, binucleate protozoan responsible for causing giardiasis. Although numerous snoRNAs have been detected in Giardia, their investigation remains limited. Nevertheless, they have been found to play a crucial role in the rRNA precursor processing pathway and influence other cellular functions. In addition, it has been proposed that some microRNAs are generated from these snoRNAs through excision by the Giardia endoribonuclease Dicer. These microRNAs are believed to contribute to the regulation of antigenic variation, which allows the parasite to evade the host immune response. Specifically, they play a role in modulating variant-specific surface proteins (VSPs) and other cysteine-rich surface antigens (CSAs). The main objective of this study was to bring together the available data on snoRNAs in Giardia, uncovering their functions in various processes and their importance on a global scale. In addition, the research delved into potential microRNAs speculated to originate from snoRNAs, exploring their impact on cellular processes.

Analyzing roles of small nucleolar RNA host gene 25 from clinical, molecular target and tumor formation in prostate cancer.

BACKGROUND: Prostate cancer (PCa) is one of the most deadly and metastatic cancers of the urinary tract. Latest studies have confirmed that long non-coding RNAs (lncRNAs) play a crucial role in a variety of cancers. Some of these lncRNAs code for small nucleolar RNAs (snoRNAs), called small nucleolar RNA host genes (SNHGs), which exert some value in predicting the prognosis of certain cancer patients, but little is known regarding the function of SNHGs within the PCa. AIM OF THE STUDY: To explore the expression distribution and differential analysis of SNHGs in different tumors using RNA-seq and survival data from TCGA and GTEx, and to assess the potential impacts of the lncRNA SNHG25 on human PCa. To validate the expression of SNHG25 using experimental data and to investigate in detail its particular molecular biological function on PCa both in vivo and in vitro. METHODS: LncRNA SNHG25 expression was analyzed by bioinformatic prediction and qPCR. CCK-8, EdU, transwell, wound healing, and western blotting assays were conducted to investigate the main role of lncRNA SNHG25 in PCa. Xenograft tumour growth model in nude mice was surveyed by in vivo imaging and Ki-67 staining. AKT pathway activator (SC79) was used to verify the interaction among SNHG25 and PI3K/AKT signaling pathway. RESULTS: Bioinformatics analysis and experimental research illuminated that the expression of lncRNA SNHG25 was observably up-regulated in PCa tissues and cells. Moreover, SNHG25 knockdown restrained PCa cell proliferation, invasion and migration, while promoting apoptosis. Xenografts model confirmed that the si-SNHG25 group had a significant inhibitory effect on PCa tumour growth in vivo. Additionally, a series of gain-of-function analyses suggested that SNHG25 could activate the PI3K/AKT pathway to accelerate PCa progression. CONCLUSIONS: These in vitro and in vivo findings demonstrate that SNHG25 is highly expressed in PCa and facilitates PCa development through regulation of PI3K/AKT signaling pathway. SNHG25 acts as an oncogene to predict tumour malignancy and survival in PCa patients and may therefore become a promising potential molecular target for early detection and therapy of lethal PCa.

Posttranscriptional Regulation by Proteins and Noncoding RNAs.

Posttranscriptional regulation comprises those mechanisms occurring after the initial copy of the DNA sequence is transcribed into an intermediate RNA molecule (i.e., messenger RNA) until such a molecule is used as a template to generate a protein. A subset of these posttranscriptional regulatory mechanisms essentially are destined to process the immature mRNA toward its mature form, conferring the adequate mRNA stability, providing the means for pertinent introns excision, and controlling mRNA turnover rate and quality control check. An additional layer of complexity is added in certain cases, since discrete nucleotide modifications in the mature RNA molecule are added by RNA editing, a process that provides large mature mRNA diversity. Moreover, a number of posttranscriptional regulatory mechanisms occur in a cell- and tissue-specific manner, such as alternative splicing and noncoding RNA-mediated regulation. In this chapter, we will briefly summarize current state-of-the-art knowledge of general posttranscriptional mechanisms, while major emphases will be devoted to those tissue-specific posttranscriptional modifications that impact on cardiac development and congenital heart disease.

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.

SNORD60 promotes the tumorigenesis and progression of endometrial cancer through binding PIK3CA and regulating PI3K/AKT/mTOR signaling pathway.

Endometrial carcinoma is a common gynecological malignant tumor, small nucleolar RNAs (snoRNAs) are involved in cancer development. However, researches on the roles of snoRNAs in endometrial carcinoma are limited. The expression levels of snoRNAs in endometrial cancer tissues were analyzed using The Cancer Genome Atlas (TCGA) database. Antisense oligonucleotides (ASOs) and plasmids were used for transfection. Moreover, CCK-8, EdU, wound-healing assay, transwell, cell apoptosis, western blotting, and xenograft model were employed to examine the biological functions of related molecules. real-time reverse transcription polymerase chain reaction and western blotting were performed to detect messenger RNA (mRNA) and protein levels. Including bioinformatics, fluorescence in situ hybridization, RNA pulldown, actinomycin D and RTL-P assays were also carried out to explore the molecular mechanism. Analysis of data from TCGA showed that the expression level of small nucleolar RNA, C/D box 60 (SNORD60) in endometrial cancer tissues is observably higher than that in normal endometrial tissues. Further research suggested that SNORD60 played a carcinogenic role both in vitro and in vivo, and significantly upregulated the expression of PIK3CA. However, the carcinogenic effects can be reversed by knocking down fibrillarin (FBL) or PIK3CA. SNORD60 forms complexes by binding with 2'-O-methyltransferase fibrillarin, thus catalyzes the 2'-O-methylation (Nm) modification of PIK3CA mRNA and modulates the PI3K/AKT/mTOR signaling pathway, so as to promote the development of endometrial cancer. In short, SNORD60 might become a new biomarker for the therapy of endometrial cancer in the future and provide new strategies for diagnosis and treatment.

A three-snoRNA signature: SNORD15A, SNORD35B and SNORD60 as novel biomarker for renal cell carcinoma.

BACKGROUND: Accumulating evidence has confirmed the role of snoRNAs in a variety of cancer, but rare in renal cell carcinoma (RCC). This study aims to clarify the role of snoRNAs in RCC tumorigenesis and their potential as novel tumor biomarkers. MATERIALS AND METHODS: The snoRNA expression matrix was obtained from the public TCGA and SNORic databases. SNORD15A, SNORD35B and SNORD60 were selected and validated by qPCR, then analyzed combined with related clinical factors using T-test and ROC curve. RESULTS: All three snoRNAs: SNORD15A, SNORD35B and SNORD60 were significantly upregulated in cancer tissues compared to adjacent tissues from TCGA or FFPE detection. These three snoRNAs were also increased in urinary sediment (US) of RCC as well as the early-stage RCC patients compared with the healthy controls. In addition, RNase stability experiments confirmed their stable existence in US. Meanwhile, the ROC curve shows that SNORD15A, SNORD35B and SNORD60 could effectively distinguish RCC (AUC = 0.7421) and early-stage RCC (AUC = 0.7465) from healthy individuals. CONCLUSION: SNORD15A, SNORD35B and SNORD60 were upregulated in tissues and US of RCC, serving as novel potential biomarkers for RCC diagnosis.

Modulation of the Drosophila transcriptome by developmental exposure to alcohol.

BACKGROUND: Prenatal exposure to ethanol can cause fetal alcohol spectrum disorder (FASD), a prevalent, preventable pediatric disorder. Identifying genetic risk alleles for FASD is challenging since time, dose, and frequency of exposure are often unknown, and manifestations of FASD are diverse and evident long after exposure. Drosophila melanogaster is an excellent model to study the genetic basis of the effects of developmental alcohol exposure since many individuals of the same genotype can be reared under controlled environmental conditions. RESULTS: We used 96 sequenced, wild-derived inbred lines from the Drosophila melanogaster Genetic Reference Panel (DGRP) to profile genome-wide transcript abundances in young adult flies that developed on ethanol-supplemented medium or standard culture medium. We found substantial genetic variation in gene expression in response to ethanol with extensive sexual dimorphism. We constructed sex-specific genetic networks associated with alcohol-dependent modulation of gene expression that include protein-coding genes, Novel Transcribed Regions (NTRs, postulated to encode long non-coding RNAs) and female-specific coordinated regulation of snoRNAs that regulate pseudouridylation of ribosomal RNA. We reared DGRP lines which showed extreme upregulation or downregulation of snoRNA expression during developmental alcohol exposure on standard or ethanol supplemented medium and demonstrated that developmental exposure to ethanol has genotype-specific effects on adult locomotor activity and sleep. CONCLUSIONS: There is significant and sex-specific natural genetic variation in the transcriptional response to developmental exposure to ethanol in Drosophila that comprises networks of genes affecting nervous system development and ethanol metabolism as well as networks of regulatory non-coding RNAs.

RNA folding and functions of RNA helicases in ribosome biogenesis.

Eukaryotic ribosome biogenesis involves the synthesis of ribosomal RNA (rRNA) and its stepwise folding into the unique structure present in mature ribosomes. rRNA folding starts already co-transcriptionally in the nucleolus and continues when pre-ribosomal particles further maturate in the nucleolus and upon their transit to the nucleoplasm and cytoplasm. While the approximate order of folding of rRNA subdomains is known, especially from cryo-EM structures of pre-ribosomal particles, the actual mechanisms of rRNA folding are less well understood. Both small nucleolar RNAs (snoRNAs) and proteins have been implicated in rRNA folding. snoRNAs hybridize to precursor rRNAs (pre-rRNAs) and thereby prevent premature folding of the respective rRNA elements. Ribosomal proteins (r-proteins) and ribosome assembly factors might have a similar function by binding to rRNA elements and preventing their premature folding. Besides that, a small group of ribosome assembly factors are thought to play a more active role in rRNA folding. In particular, multiple RNA helicases participate in individual ribosome assembly steps, where they are believed to coordinate RNA folding/unfolding events or the release of proteins from the rRNA. In this review, we summarize the current knowledge on mechanisms of RNA folding and on the specific function of the individual RNA helicases involved. As the yeast Saccharomyces cerevisiae is the organism in which ribosome biogenesis and the role of RNA helicases in this process is best studied, we focused our review on insights from this model organism, but also make comparisons to other organisms where applicable.

Plasma SNORD83A as a potential biomarker for early diagnosis of non-small-cell lung cancer.

Aim: This study aimed to access the efficacy of plasma small nucleolar RNAs in early diagnosis of non-small-cell lung cancer (NSCLC). Methods: SNORD83A was selected based on databases and further verified in 48 paired formalin-fixed, paraffin-embedded tissues, as well as in plasma from 150 NSCLC patients and 150 healthy donors. The diagnostic efficiency of plasma SNORD83A, as well as in combination with carcinoembryonic antigen, was determined by receiver operating characteristic analysis. Results: SNORD83A was significantly increased not only in tissues but also in plasma from NSCLC patients compared with those from healthy donors. Plasma SNORD83A was able to act as a diagnostic biomarker for NSCLC. The diagnostic efficiency of carcinoembryonic antigen was also significantly elevated for early-stage NSCLC when combined with SNORD83A. Conclusion: SNORD83A can serve as a diagnostic biomarker for NSCLC.

Plasma SNORD42B and SNORD111 as potential biomarkers for early diagnosis of non-small cell lung cancer.

BACKGROUND: Non-small-cell lung cancer (NSCLC) still occupied the leading reason of cancer death due to lack of availability of early detection. This study aimed to identify the effective biomarkers for the early-stage NSCLC diagnostics based on plasma snoRNAs. MATERIALS AND METHODS: The differential snoRNAs between lung cancer patients and healthy donors were analyzed using the SNORic and TCGA databases. SNORD42B and SNORD111 were screened out and further verified in 48 FFPE NSCLC and adjacent normal tissues, as well as in plasma from 165 NSCLC patients and 118 health donors using qRT-PCR. Next, their diagnostic efficiency, as well as combined with carcinoembryonic antigen (CEA), was obtained by the analysis of receiver operating characteristic (ROC). RESULTS: We first screened out 47 top differential snoRNAs, among which the top 10 upregulated snoRNAs in LUAD were U44, U75, U78, U77, SNORD72, SNORD13, SNORD12B, SCARNA5, U80, SNORD41, and in LUSC were U44, U75, U78, SNORD41, SNORD111, SNORA56, U17a, SNORD35A, SNORD32A, SNORA71D. SNORD42B and SNORD111 was significantly increased not only in tumor tissues but also in plasma from NSCLC and early-stage NSCLC patients. They were capable to act as promising biomarkers for NSCLC and early-stage NSCLC diagnosis. Moreover, CEA diagnostic efficiency for early-stage NSCLC was significantly improved when combined with these two plasma snoRNAs. CONCLUSION: SNORD42B and SNORD111 could act as the potential and non-invasive diagnostic biomarkers for NSCLC and early-stage NSCLC.

Analysis of Expression Pattern of snoRNAs in Human Cells A549 Infected by Influenza A Virus.

Small nucleolar RNAs (snoRNAs) are a highly expressed class of non-coding RNAs known for their role in guiding post-transcriptional modifications of ribosomal RNAs and small nuclear RNAs. Emerging studies suggest that snoRNAs are also implicated in regulating other vital cellular processes, such as pre-mRNA splicing and 3'-processing of mRNAs, and in the development of cancer and viral infections. There is an emerging body of evidence for specific snoRNA's involvement in the optimal replication of RNA viruses. In order to investigate the expression pattern of snoRNAs during influenza A viral infection, we performed RNA sequencing analysis of the A549 human cell line infected by influenza virus A/Puerto Rico/8/1934 (H1N1). We identified 66 that were upregulated and 55 that were downregulated in response to influenza A virus infection. The increased expression of most C/D-box snoRNAs was associated with elevated levels of 5'- and 3'-short RNAs derived from this snoRNA. Analysis of the poly(A)+ RNA sequencing data indicated that most of the differentially expressed snoRNAs synthesis was not correlated with the corresponding host genes expression. Furthermore, influenza A viral infection led to an imbalance in the expression of genes responsible for C/D small nucleolar ribonucleoprotein particles' biogenesis. In summary, our results indicate that the expression pattern of snoRNAs in A549 cells is significantly altered during influenza A viral infection.

Death by lipids: The role of small nucleolar RNAs in metabolic stress.

Excess fatty acid accumulation in nonadipose tissues leads to cell dysfunction and cell death that is linked to the pathogenesis of inherited and acquired human diseases. Study of this process, known as lipotoxicity, has provided new insights into the regulation of lipid homeostasis and has revealed new molecular pathways involved in lipid-induced cellular stress. The discovery that disruption of specific small nucleolar RNAs protects against fatty acid-induced cell death and remodels metabolism in vivo opens new opportunities for understanding how nutrient signals influence cellular and systemic metabolic homeostasis through RNA biology.

SnoRNA copy regulation affects family size, genomic location and family abundance levels.

BACKGROUND: Small nucleolar RNAs (snoRNAs) are an abundant class of noncoding RNAs present in all eukaryotes and best known for their involvement in ribosome biogenesis. In mammalian genomes, many snoRNAs exist in multiple copies, resulting from recombination and retrotransposition from an ancestral snoRNA. To gain insight into snoRNA copy regulation, we used Rfam classification and normal human tissue expression datasets generated using low structure bias RNA-seq to characterize snoRNA families. RESULTS: We found that although box H/ACA families are on average larger than box C/D families, the number of expressed members is similar for both types. Family members can cover a wide range of average abundance values, but importantly, expression variability of individual members of a family is preferred over the total variability of the family, especially for box H/ACA snoRNAs, suggesting that while members are likely differentially regulated, mechanisms exist to ensure uniformity of the total family abundance across tissues. Box C/D snoRNA family members are mostly embedded in the same host gene while box H/ACA family members tend to be encoded in more than one different host, supporting a model in which box C/D snoRNA duplication occurred mostly by cis recombination while box H/ACA snoRNA families have gained copy members through retrotransposition. And unexpectedly, snoRNAs encoded in the same host gene can be regulated independently, as some snoRNAs within the same family vary in abundance in a divergent way between tissues. CONCLUSIONS: SnoRNA copy regulation affects family sizes, genomic location of the members and controls simultaneously member and total family abundance to respond to the needs of individual tissues.