Identifying key regulatory networks and predicting targets of orphan box C/D SNORD116 snoRNAs in Prader-Willi Syndrome
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA971186 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24495917_1.fastq.gz | Fastqsanger.gz | |||
| SRR24495917_2.fastq.gz | Fastqsanger.gz | |||
| SRR24495918_1.fastq.gz | Fastqsanger.gz | |||
| SRR24495918_2.fastq.gz | Fastqsanger.gz | |||
| SRR24495919_1.fastq.gz | Fastqsanger.gz |
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Project description:To identify the targets and functions of SNORD116 snoRNAs, we engineered two different deletions mimicking those seen in Prader-Willi Syndrome (PWS) patients into two distinct human embryonic stem cell lines to control for effects of genetic background. We also introduced an inducible Neurogenin-2 cassette into the safe-harbor AAVS1 locus to enable quick and reproducible differentiation into neurons. We verified wild type and deletion genotypes across both genetic background generated comparable neruons at a gene expression level by comparing them to wild type hESCs. We then performed differential gene expression analysis using data obtained from bulk RNA-sequencing to compare the two distinct deletion types to their isogenic wild type pair and each other.
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Project description:Prader-Willi syndrome shows features linked to brain development and hypothalamus-related endocrine abnormalities. The smallest clinical deletions fall within the large (∼650Kb) SNHG14 gene, removing 29 consecutive introns that each generate SNORD116. SNHG14 also includes 48 tandem introns encoding SNORD115 and generates multiple, extended snoRNA-related species. SNORD115 and SNORD116 resemble box C/D small nucleolar RNAs (snoRNAs) but lack known targets. Both snoRNAs strongly accumulated during neuronal differentiation. SNORD116 accumulation apparently reflected stabilization, potentially linked to the appearance of FBLL1, a homologue of the ubiquitous snoRNA-associated protein Fibrillarin (FBL). In contrast, SNORD115 was selectively transcribed, apparently due to regulated termination. For functional characterization we created cell lines lacking only the expressed, paternal, SNORD115 or SNORD116 cluster. Analyses during neuronal development indicated changes in RNA stability and protein synthesis. Altered mRNAs included MAGEL2, mutation of which causes the PWS-like disorder Schaaf-Yang syndrome. Comparison of SNORD115 and SNORD116 mutants indicated overlapping or interacting functions. Most changes in mRNA and protein abundance appeared relatively late in development, with roles including cytoskeleton formation, extracellular matrix, neuronal arborization. Comparison with human embryonic midbrain development suggested enhanced progression in neuronal development in the snoRNA mutants. Subtle impairment of relative neuronal maturation during development, might generate the clinical phenotypes.
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Project description:In the snoRNA host gene SNHG14, 29 consecutive introns each generate SNORD116, and 48 tandem introns encode SNORD115. Loss of SNORD116 expression, but not of SNORD115, is linked to the neurodevelopmental disease Prader-Willi syndrome. SNORD116 and SNORD115 resemble box C/D small nucleolar RNAs (snoRNAs) but lack known targets. Both were strongly accumulated during neuronal differentiation, but with distinct mechanisms: Increased host-gene expression for SNORD115 and apparent stabilization for SNORD116. For functional characterization we created cell lines specifically lacking the expressed, paternally inherited, SNORD115 or SNORD116 cluster. Analyses during neuronal development indicated changes in RNA stability and protein synthesis. These data suggested that the loss of SNORD116 enhanced some aspects of developmental timing of neuronal cells. Depleted mRNAs included MAGEL2, causal in the PWS-like disorder Schaaf-Yang syndrome. Comparison of SNORD115 and SNORD116 mutants identified small numbers of altered mRNAs and ncRNAs. These were enriched for functions potentially linked to PWS phenotypes.
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Project description:Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder characterized by neonatal hypotonia, followed by hyperphagia and obesity. Most PWS cases exhibit megabase-scale deletions of paternally imprinted 15q11-q13 locus. However, several PWS patients have been identified harboring much smaller deletions encompassing the SNORD116 gene cluster, suggesting these genes are direct drivers of PWS phenotypes. This cluster contains 30 copies of individual SNORD116 C/D box small nucleolar RNAs (snoRNAs). Many C/D box snoRNAs have been shown to guide chemical modifications of RNA molecules, often ribosomal RNA (rRNA). Conversely, SNORD116 snoRNAs show no significant complementarity to rRNA and their targets are unknown. Since many reported PWS cases lack their expression, it is crucial to identify the targets and functions of SNORD116. To address this we modeled PWS in two distinct human embryonic stem cell (hESC) lines with two different sized deletions, differentiated each into neurons, and compared differential gene expression. This analysis identified a novel set of 42 consistently dysregulated genes. These genes were significantly enriched for predicted SNORD116 targeting and we demonstrated impacts on FGF13 protein levels. Our results demonstrate the need for isogenic background comparisons and indicate a novel gene regulatory network controlled by SNORD116 is likely perturbed in PWS patients.
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Project description:ERG-related B cell precursor acute lymphoblastic leukemia (BCP ALL) is a recently described childhood ALL subtype characterized by aberrant ERG protein expression and highly recurrent ERG intragenic deletions. Several studies reported a remarkably favourable outcome for ERG-related BCP-ALL despite a high incidence of apparently inauspicious IKZF1 aberrations. In this study we investigated by integrative genomic analysis the main features of the ERG-related group in a cohort of B-others BCP ALL patients enrolled in the AIEOP ALL 2000 therapeutic protocol. We report a specific microRNA and snoRNA signature that characterizes ERG-related patients with up-regulation of the miR-125b-2 cluster on chromosome 21 and several snoRNAs in the Prader-Willi locus at 15q11.2, including the orphan SNORD116 cluster. Given the current lack of parameters for a comprehensive classification we suggest toexploit the noncoding RNAs signature for differential diagnosis of ERG-related patients.
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Project description:Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder characterized principally by initial symptoms of neonatal hypotonia and failure-to-thrive in infancy, followed by hyperphagia and obesity. It is well established that PWS is caused by loss of paternal expression of the imprinted region on chromosome 15q11-q13. While most PWS cases exhibit megabase-scale deletions of the paternal chromosome 15q11-q13 allele, several PWS patients have been identified harboring a much smaller deletion encompassing primarily SNORD116. This finding suggests SNORD116 is a direct driver of PWS phenotypes. The SNORD116 gene cluster is composed of 30 copies of individual SNORD116 C/D box small nucleolar RNAs (snoRNAs). Many C/D box snoRNAs have been shown to guide chemical modifications of other RNA molecules, often ribosomal RNA (rRNA). However, SNORD116 snoRNAs are termed 'orphans' because no verified targets have been identified and their sequences show no significant complementarity to rRNA. It is crucial to identify the targets and functions of SNORD116 snoRNAs because all reported PWS cases lack their expression. To address this, we engineered two different deletions modelling PWS in two distinct human embryonic stem cell (hESC) lines to control for effects of genetic background. Utilizing an inducible expression system enabled quick, reproducible differentiation of these lines into neurons. Systematic comparisons of neuronal gene expression across deletion types and genetic backgrounds revealed a novel list of 42 consistently dysregulated genes. Employing the recently described computational tool snoGloBe, we discovered these dysregulated genes are significantly enriched for predicted SNORD116 targeting versus multiple control analyses. Importantly, our results showed it is critical to use multiple isogenic cell line pairs, as this eliminated many spuriously differentially expressed genes. Our results indicate a novel gene regulatory network controlled by SNORD116 is likely perturbed in PWS patients.
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