RNA exosome mutations in pontocerebellar hypoplasia alter ribosome biogenesis and p53 levels
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ABSTRACT:
PROVIDER: PRJNA635887 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11874800_1.fastq.gz | Fastqsanger.gz | |||
| SRR11874800_2.fastq.gz | Fastqsanger.gz | |||
| SRR11874801_1.fastq.gz | Fastqsanger.gz | |||
| SRR11874801_2.fastq.gz | Fastqsanger.gz | |||
| SRR11874802_1.fastq.gz | Fastqsanger.gz |
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Project description:The eukaryotic RNA exosome is a ubiquitously expressed complex of nine core proteins (EXOSC1-9) and associated nucleases responsible for RNA processing and degradation. Autosomal recessive mutations in EXOSC3, EXOSC8, EXOSC9 and the exosome cofactor RBM7 cause pontocerebellar hypoplasia and motor neuronopathy. To understand the importance of the exosome in neurodegeneration, we investigated the consequences of exosome mutations on RNA metabolism and cellular survival in zebrafish and human cell models. We observed that levels of mRNAs encoding p53 and ribosome biogenesis factors are upregulated in zebrafish lines with homozygous mutations of exosc8 or exosc9, respectively. In addition, exosome deficiency leads to increased levels of multiple non-coding RNAs (e.g. tRNAs, snoRNAs, scaRNAs). Consistent with higher p53 levels, mutant zebrafish have a reduced head size, smaller brain and cerebellum caused by an increased number of apoptotic cells during development. Downregulation of EXOSC9 in human cells leads to p53 protein stabilisation and G2/M cell cycle arrest. The work provides explanation for the pathogenesis of exosome-related disorders and highlights the link between exosome function, ribosome biogenesis and p53-dependent signalling.
2020-05-30 | GSE151452 | GEO
Project description:Molecular Characterization of Pontocerebellar Hypoplasia
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Project description:Molecular Characterization of Pontocerebellar Hypoplasia
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Project description:The RNA exosome is a ubiquitously expressed complex of nine core proteins (EXOSC1-9) and associated nucleases responsible for RNA processing and degradation. Mutations in EXOSC3, EXOSC8, EXOSC9, and the exosome cofactor RBM7 cause pontocerebellar hypoplasia and motor neuronopathy. We investigated the consequences of exosome mutations on RNA metabolism and cellular survival in zebrafish and human cell models. We observed that levels of mRNAs encoding p53 and ribosome biogenesis factors are increased in zebrafish lines with homozygous mutations of exosc8 or exosc9, respectively. Consistent with higher p53 levels, mutant zebrafish have a reduced head size, smaller brain, and cerebellum caused by an increased number of apoptotic cells during development. Down-regulation of EXOSC8 and EXOSC9 in human cells leads to p53 protein stabilisation and G2/M cell cycle arrest. Increased p53 transcript levels were also observed in muscle samples from patients with EXOSC9 mutations. Our work provides explanation for the pathogenesis of exosome-related disorders and highlights the link between exosome function, ribosome biogenesis, and p53-dependent signalling. We suggest that exosome-related disorders could be classified as ribosomopathies.
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Project description:Recessive mutations in EXOSC3, encoding a subunit of the human RNA exosome complex, cause Pontocerebellar hypoplasia type 1b (PCH1B). We report a boy with severe muscular hypotonia, psychomotor retardation, progressive microcephaly, and cerebellar atrophy. Biochemical abnormalities comprised mitochondrial Complex I and PDHc deficiency. Whole exome sequencing uncovered a known EXOSC3-mutation p.(D132A) as the underlying cause. In patient fibroblasts, >50% of the EXOSC3 protein was trapped in the cytosol. mtDNA-copy numbers in muscle were reduced to 40%, but mutations in the mtDNA and nuclear mitochondrial genes were excluded. RNA-seq of patient muscle showed highly increased mRNA-copy numbers, especially for genes encoding structural subunits of OXPHOS-complexes I, III, and IV, possibly due to reduced degradation by a dysfunctional exosome complex. This is the first case of mitochondrial dysfunction associated with an EXOSC3 mutation, which expands the phenotypic spectrum of PCH1B. We discuss the links between exosome and mitochondrial dysfunction.
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Project description:A Drosophila Model of Pontocerebellar Hypoplasia Reveals a Critical Role for the RNA Exosome in Neurons
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Project description:Intracellular ribonucleases (RNases) are essential in all aspects of RNA metabolism, including maintaining accurate RNA levels. Inherited mutations in genes encoding ubiquitous RNases are associated with human diseases, primarily affecting the nervous system. Recessive mutations in genes encoding an evolutionarily conserved RNase complex, the RNA exosome, lead to syndromic neurodevelopmental disorders characterized by progressive neurodegeneration, such as Pontocerebellar Hypoplasia Type 1b (PCH1b). We establish a CRISPR/Cas9-engineered Drosophila model of PCH1b to study cell-type-specific post-transcriptional regulatory functions of the nuclear RNA exosome complex within fly head tissue. Here, we report that pathogenic RNA exosome mutations alter activity of the complex, causing widespread dysregulation of brain-enriched cellular transcriptomes, including rRNA processing defects—resulting in tissue-specific, progressive neurodegenerative effects in flies. These findings provide a comprehensive understanding of RNA exosome function within a developed animal brain and underscore the critical role of post-transcriptional regulatory machinery in maintaining cellular RNA homeostasis within the brain.
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Project description:Cells release intraluminal vesicles (ILVs) in multivesicular bodies as exosomes to communicate with other cells. Although recent studies suggest an intimate link between exosome biogenesis and autophagy, the detailed mechanism is not fully understood. Here we employed comprehensive RNAi screening for autophagy-related factors and discovered that Rubicon, a negative regulator of autophagy, is essential for exosome release. Rubicon recruits WIPI2d to endosomes to promote exosome biogenesis. Interactome analysis of WIPI2d identified the ESCRT components that are required for ILV formation. Notably, we found that Rubicon is required for an age-dependent increase of exosome release in mice. In addition, small RNA sequencing of serum exosomes revealed that Rubicon determines the fate of exosomal microRNAs associated with aging and longevity pathways. Taken together, our current results suggest that the Rubicon-WIPI axis functions as a key regulator of exosome biogenesis and is responsible for the age-dependent changes in exosome quantity and quality.
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Project description:RNA exosomopathies, a growing family of tissue-specific diseases, are linked to missense mutations in genes encoding the structural subunits of the conserved 10-subunit exoribonuclease complex, the RNA exosome. Such mutations in the cap subunit gene EXOSC2 cause the novel syndrome SHRF (Short stature, Hearing loss, Retinitis pigmentosa and distinctive Facies). In contrast, exosomopathy mutations in the cap subunit gene EXOSC3 cause pontocerebellar hypoplasia type 1b (PCH1b). Though having strikingly different disease pathologies, EXOSC2 and EXOSC3 exosomopathy mutations result in amino acid substitutions in similar, conserved domains of the cap subunits, suggesting that these exosomopathy mutations have distinct consequences for RNA exosome function. We generated the first in vivo model of the SHRF pathogenic amino acid substitutions using budding yeast by introducing the EXOSC2 mutations in the orthologous S. cerevisiae gene RRP4. The resulting rrp4 mutant cells have defects in cell growth and RNA exosome function. We detect significant transcriptomic changes in both coding and non-coding RNAs in the rrp4 variant, rrp4-G226D, which models EXOSC2 p.Gly198Asp. Comparing this rrp4-G226D mutant to the previously studied S. cerevisiae model of EXOSC3 PCH1b mutation, rrp40-W195R, reveals that these mutants have disparate effects on certain RNA targets, providing the first evidence for different mechanistic consequences of these exosomopathy mutations. Congruently, we detect specific negative genetic interactions between RNA exosome cofactor mutants and rrp4-G226D but not rrp40-W195R. These data provide insight into how SHRF mutations could alter the function of the RNA exosome and allow the first direct comparison of exosomopathy mutations that cause distinct pathologies.
2020-12-14 | GSE163106 | GEO
Project description:Splicing is a complex process, required to create the transcriptomic diversity needed for specialised functions in higher eukaryotes. The spliceosome contains more than 100 proteins and RNA molecules which coordinate this dynamic process, and interestingly, despite the ubiquity of splicing, pathogenic variants in spliceosomal components often cause a tissue-specific phenotype, hinting at further complexities which are not yet fully understood. We have identified a cohort of ten families with de novo missense variants in a spliceosomal component, CRNKL1, where nine individuals harbour one of two missense variants that both affect the same amino acid, p.Arg267. All patients share a common and specific phenotype: profound pre- and post-natal microcephaly, with pontocerebellar hypoplasia, seizures and severe intellectual disability. Microinjection of mutant crnkl1 into a zebrafish model caused significant lack of brain development accompanied by a significant reduction in proliferating cells and widespread cellular stress, as indicated by p53 staining. RNA-seq analysis of injected zebrafish embryos showed widespread transcriptomic changes, with altered expression of neuronal and cell cycle genes. Together, we have identified CRNKL1 as a novel disease gene and demonstrate the requirement for this protein in brain development and functioning. Our findings contribute to a growing disease cluster, where components act at the same spliceosomal stage and cause a brain-specific but severe phenotype, suggesting a more intricate role for these spliceosomal subcomplexes than previously thought.
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