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Genome-wide consequences of compromised NMD and their relavence for variable clinical phenotype of patients with UPF3B mutations [CNV]

ABSTRACT: Nonsense-mediated mRNA decay (NMD) surveillance pathways are best known to be involved in the degradation of mRNA with premature termination codons (PTCs). More recent studies demonstrate that the role of NMD pathways goes well beyond the degradation of PTC containing mRNA, into the regulation of cell function and thus normal development. We have taken advantage of the availability of naturally occurring loss of function mutations in the UPF3B gene, a major component of the exon junction complex (EJC), to inquire about genome-wide consequences of compromised NMD. We identify that about 5% of the lymphoblastoid cell transcriptome is directly or indirectly impacted upon in patients with UPF3B mutations with minimal effect on alternative splicing. We identify UPF3A-NMD as a likely, major modifier of the UPF3B patient phenotype through variable UPF3A protein stabilisation. Among the most consistently deregulated direct targets of UPF3B-NMD we identify the ARHGAP24 as the most likely gene implicated in the neuronal phenotype of UPF3B patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE27412 | GEO | 2011/11/01

SECONDARY ACCESSION(S): PRJNA141835

REPOSITORIES: GEO

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Genome-wide consequences of compromised NMD and their relavence for variable clinical phenotype of patients with UPF3B mutations [mRNA profiling]

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Genome-wide consequences of compromised NMD and their relavence for variable clinical phenotype of patients with UPF3B mutations [RNA-seq]

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Genome-wide consequences of compromised NMD and their relavence for variable clinical phenotype of patients with UPF3B mutations [CNV]

Project description:Nonsense-mediated mRNA decay (NMD) surveillance pathways are best known to be involved in the degradation of mRNA with premature termination codons (PTCs). More recent studies demonstrate that the role of NMD pathways goes well beyond the degradation of PTC containing mRNA, into the regulation of cell function and thus normal development. We have taken advantage of the availability of naturally occurring loss of function mutations in the UPF3B gene, a major component of the exon junction complex (EJC), to inquire about genome-wide consequences of compromised NMD. We identify that about 5% of the lymphoblastoid cell transcriptome is directly or indirectly impacted upon in patients with UPF3B mutations with minimal effect on alternative splicing. We identify UPF3A-NMD as a likely, major modifier of the UPF3B patient phenotype through variable UPF3A protein stabilisation. Among the most consistently deregulated direct targets of UPF3B-NMD we identify the ARHGAP24 as the most likely gene implicated in the neuronal phenotype of UPF3B patients. To assess the impact of UPF3B-NMD deficiency on human transcriptome, we sequenced polyA RNA extracted from lymphoblastoid cell lines of patients (n=4) and controls (n=2). We complemented the analysis using Affymetrix Human Exon 1.0 St array using total RNA of the same cell line from patients (n=5, 3 of whom were also sequenced) and controls (n=5). Moreover, we overlapped identified differently expressed genes with copy number variation data of the patients, obtained using Illumina Human Omniexpress chip, to exclude possible false positive.

2011-11-01 | E-GEOD-27412 | biostudies-arrayexpress

Genome-wide consequences of compromised NMD and their relavence for variable clinical phenotype of patients with UPF3B mutations [mRNA profiling]

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Genome-wide consequences of compromised NMD and their relavence for variable clinical phenotype of patients with UPF3B mutations [RNA-seq]

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Genome-wide consequences of compromised NMD and their relavence for variable clinical phenotype of patients with UPF3B mutations

Project description:This SuperSeries is composed of the following subset Series: GSE27125: Genome-wide consequences of compromised NMD and their relavence for variable clinical phenotype of patients with UPF3B mutations [mRNA profiling] GSE27199: Genome-wide consequences of compromised NMD and their relavence for variable clinical phenotype of patients with UPF3B mutations [RNA-seq] GSE27412: Genome-wide consequences of compromised NMD and their relavence for variable clinical phenotype of patients with UPF3B mutations [CNV] Refer to individual Series

2011-11-01 | E-GEOD-27433 | biostudies-arrayexpress

Mammalian UPF3A and UPF3B activate NMD independently of their EJC binding

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Project description:The UPF3B-dependent branch of the nonsense-mediated RNA decay (NMD) pathway is critical for human cognition. Here, we examined the role of UPF3B in the olfactory system. Single-cell RNA-sequencing (scRNA-seq) analysis demonstrated considerable heterogeneity of olfactory sensory neuron (OSN) cell populations in wild type (WT) mice, and revealed that UPF3B loss influences specific subsets of these cell populations. UPF3B also regulates the expression of a large cadre of anti-microbial genes in OSNs, and promotes the selection of specific olfactory receptor (Olfr) genes for expression in mature OSNs (mOSNs). RNA-seq and Ribotag analyses identified classes of mRNAs expressed and translated at different levels in WT and Upf3b-null mOSNs. Integrating multiple computational approaches, UPF3B-dependent NMD target transcripts that are candidates to mediate the functions of NMD in mOSNs were identified in vivo. Together, our data provides a valuable resource for the olfactory field and insights into the roles of NMD in vivo.

2020-08-13 | GSE146043 | GEO

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