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RNA-seq of mouse P19 half-life samples upon loss of UPF3A

ABSTRACT: Gene duplication is a major evolutionary force driving adaptation and speciation, as it allows for the acquisition of new functions and can augment or diversify existing functions. Here, we report a gene duplication event that yielded another outcome – the generation of antagonistic functions. One product of this duplication event – UPF3B – is critical for the nonsense-mediated RNA decay (NMD) pathway, while its autosomal counterpart – UPF3A – encodes an enigmatic protein previously shown to have trace NMD activity. Using loss-of-function approaches in vitro and in vivo, we discovered that UPF3A acts primarily as a potent NMD inhibitor that stabilizes hundreds of transcripts. Evidence suggests that UPF3A acquired repressor activity through simple impairment of a critical domain, a rapid mechanism that may have been widely used in evolution. Mice conditionally lacking UPF3A exhibit “hyper” NMD and display defects in embryogenesis and gametogenesis, consistent with UPF3A serving as a molecular rheostat that directs developmental events.

ORGANISM(S): Mus musculus

PROVIDER: GSE77262 | GEO | 2016/03/31

SECONDARY ACCESSION(S): PRJNA309898

REPOSITORIES: GEO

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RNA-seq of mouse P19 half-life samples upon loss of UPF3A

Project description:Gene duplication is a major evolutionary force driving adaptation and speciation, as it allows for the acquisition of new functions and can augment or diversify existing functions. Here, we report a gene duplication event that yielded another outcome â the generation of antagonistic functions. One product of this duplication event â UPF3B â is critical for the nonsense-mediated RNA decay (NMD) pathway, while its autosomal counterpart â UPF3A â encodes an enigmatic protein previously shown to have trace NMD activity. Using loss-of-function approaches in vitro and in vivo, we discovered that UPF3A acts primarily as a potent NMD inhibitor that stabilizes hundreds of transcripts. Evidence suggests that UPF3A acquired repressor activity through simple impairment of a critical domain, a rapid mechanism that may have been widely used in evolution. Mice conditionally lacking UPF3A exhibit âhyperâ NMD and display defects in embryogenesis and gametogenesis, consistent with UPF3A serving as a molecular rheostat that directs developmental events. â Examination of transcript stability with loss of UPF3A in mouse P19 cells.

2016-03-31 | E-GEOD-77262 | biostudies-arrayexpress

The role of the NMD factor UPF3B in olfactory sensory neurons

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

Dosage imbalance of NMD genes is associated with intellectual disability

Project description:Nonsense-mediated mRNA decay (NMD) functions to degrade transcripts bearing premature stop codon (PTC) and is a crucial regulator of gene expression. NMD and the UPF3B gene have been implicated as the cause of various forms of intellectual disability (ID) and other neurological symptoms. Here, we reports three patients with global developmental delay carrying hemizygous deletions of the UPF2 gene, another important member of the NMD pathway and direct interacting partner of UPF3B.

2012-12-31 | GSE35420 | GEO

Deciphering the cellular roles and dissecting functional regions of UPF3A and UPF3B in human NMD

Project description:The paralogous proteins UPF3A and UPF3B are involved in recognizing defective mRNAs that are degraded by nonsense-mediated mRNA decay (NMD). While UPF3B has been demonstrated to support NMD, UPF3A was reported to act either an NMD activator or an NMD inhibitor. Here, we present a comprehensive functional analysis of UPF3A and UPF3B in human cells using overexpression, knockdowns, knockouts (KO) and rescue experiments. Overexpression or knockout of UPF3A did not result in detectable changes in global NMD activity or other specific transcriptome alterations . NMD activity was also virtually unchanged in UPF3B KO cells. In contrast, the co-depletion or co-knockout of UPF3A and UPF3B resulted in a marked NMD inhibition and a global upregulation of PTC-containing transcripts. In rescue experiments UPF3B was fully functional when either UPF2- or EJC binding was impaired . However, the deletion of both interaction sites or one interaction site and a central region of UPF3B impaired its NMD function. Altogether, our work identifies critical functional domains of UPF3B and establishes redundant roles of UPF3A and UPF3B during NMD.

2022-05-04 | PXD027120 | Pride

A Upf3b-mutant mouse model with behavioral and neurogenesis defects

Project description:Nonsense-mediated RNA decay (NMD) is a highly conserved and selective RNA degradation pathway that acts on RNAs terminating their reading frames in specific contexts. NMD is regulated in a tissue-specific and developmentally controlled manner, raising the possibility that it influences developmental events. Indeed, loss or depletion of NMD factors have been shown to disrupt developmental events in organisms spanning the phylogenetic scale. In humans, mutations in the NMD factor gene, UPF3B, causes intellectual disability (ID) and are strongly associated with autism spectrum (ASD), attention deficit hyperactivity disorder (ADHD), and schizophrenia (SCZ). Here, we report the generation and characterization of mice harboring a null Upf3b allele. These Upf3b-null mice exhibit deficits in fear-conditioned learning, but not spatial learning. Upf3b-null mice also have a profound defect in prepulse inhibition (PPI), a measure of sensorimotor gating commonly deficient in individuals with SCZ and other brain disorders. Consistent with both their PPI and learning defects, cortical pyramidal neurons from Upf3b-null mice display deficient dendritic spine maturation in vivo. In addition, neural stem cells from Upf3b-null mice have impaired ability to undergo differentiation and they require prolonged culture to give rise to functional neurons with electrical activity. RNA sequencing (RNAseq) analysis of the frontal cortex identified UPF3B- regulated RNAs, including direct NMD target transcripts encoding proteins with known functions in neural differentiation, maturation, and disease. We suggest that Upf3b-null mice serves as a novel model system to decipher cellular and molecular defects underlying ID and neuro-developmental disorders.

2018-04-09 | GSE99112 | GEO

RNA-Seq of WT Flp-In T-REx 293, UPF3B knockout and UPF3A-UPF3B double knockout cell lines with additional siRNA-mediated control or UPF3B knockdowns

Project description:UPF3A and UPF3B are paralogous genes in human cells that are involved in the nonsense-mediated decay (NMD) pathway. NMD is a cellular quality control mechanism that monitors mRNAs during translation. Aberrant translation due to features such as the presence of a premature stop codon downstream on an exon-exon junction activates NMD and leads to the degradation of the mRNA. To investigate the role of UPF3B and UPF3A in NMD, we have generated UPF3B knockout (KO) and UPF3A-UPF3B double KO (dKO) human Flp-In T-REx 293 cells using CRISPR-Cas9. We generated RNA-Sequencing data for wildtype, UPF3B KO and UPF3A-UPF3B dKO cells with additional siRNA-mediated knockdown of Luciferase (Luc) as control or UPF3B.

2022-04-25 | E-MTAB-10716 | biostudies-arrayexpress

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

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.

2011-11-01 | GSE27199 | GEO

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

2011-11-01 | GSE27125 | GEO

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

2011-11-01 | GSE27412 | GEO

Proximity labelling of FLAG-TurboID-tagged UPF3B wild type and interaction-deficient mutant proteins followed by proteomics analysis

Project description:UPF3A and UPF3B are paralogous genes in human cells that are involved in the nonsense-mediated decay (NMD) pathway. NMD is a cellular quality control mechanism that monitors mRNAs during translation. Aberrant translation due to features such as the presence of a premature stop codon downstream on an exon-exon junction activates NMD and leads to the degradation of the mRNA. To investigate the role of UPF3B in NMD, we have generated FLAG-TurboID-UPF3B wild type or mutant expressing human Flp-In T-Rex 293 UPF3B knockout cells using the PiggyBac transposon system. We generated proteomic data from the proximity labeled interactome of these UPF3B variants.

2022-05-04 | PXD029898 | Pride

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