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Series GSE151452 Query DataSets for GSE151452
Status Public on May 30, 2020
Title RNA exosome mutations in pontocerebellar hypoplasia alter ribosome biogenesis and p53 levels
Organisms Danio rerio; Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary 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.
Overall design RNAseq case - control analysis of Human induced Neuronal Progenitor Cells (iNPCs) and CRISPR/cas9 Zebrafish embryos. Human fibroblasts with recessive mutations in EXOSC3, EXOSC8 or EXOSC9 and three different healthy contols were reprogrammed to iNPCs and sequenced with total RNAseq. Zebrafish embryos homozygous for CRISPR/cas9 induced mutations in exosc8 or exosc9 underwent total RNA sequencing along with three sets of non-mutant embyo controls. Sequencng was performed on three biological replicates of all samples across four lanes of an Illumina HiSeq 2500 platform.
Contributor(s) Griffin HR, Mueller JS, Burns DT, Wells GR, Munro B, Schneider C, Horvath R
Citation(s) 32527837
Submission date May 29, 2020
Last update date Jun 29, 2020
Contact name Helen R Griffin
Phone 07531816860
Organization name Newcastle University
Street address William Leech Building, Floor 3, Medical School
City Newcatle Upon Tyne
ZIP/Postal code NE2 4HH
Country United Kingdom
Platforms (2)
GPL16791 Illumina HiSeq 2500 (Homo sapiens)
GPL18413 Illumina HiSeq 2500 (Danio rerio)
Samples (108)
GSM4578696 EXOSC3-NPC-1-L001
GSM4578697 EXOSC3-NPC-1-L002
GSM4578698 EXOSC3-NPC-1-L003
BioProject PRJNA635887
SRA SRP265271

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Supplementary file Size Download File type/resource
GSE151452_RAW.tar 17.6 Mb (http)(custom) TAR (of TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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