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Differentially expressed genes and transcript isoforms in mouse NSCs expressing miR-128

ABSTRACT: We identify a brain-specific microRNA—miR-128—that represses Nonsense Mediated mRNA Decay (NMD) and thereby controls batteries of transcripts in neural cells. miR-128 represses NMD by targeting the RNA helicase UPF1 and the exon-junction complex core component MLN51. We employed exon arrays for this analysis, as this platform detects expression levels of individual exons and thus allows detection of not only differentially expressed transcripts (DETs), but also alternative isoform transcripts (AITs). The latter is particularly relevant to our study because alternative RNA processing events (e.g., RNA splicing, alternative promoter usage, and alternative polyadenylation-site usage) often place a translation termination codon in a premature context and thereby trigger NMD.

ORGANISM(S): Mus musculus

PROVIDER: GSE28889 | GEO | 2011/04/28

SECONDARY ACCESSION(S): PRJNA140641

REPOSITORIES: GEO

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Differentially expressed genes and transcript isoforms in mouse NSCs expressing miR-128

Project description:We identify a brain-specific microRNA—miR-128—that represses Nonsense Mediated mRNA Decay (NMD) and thereby controls batteries of transcripts in neural cells. miR-128 represses NMD by targeting the RNA helicase UPF1 and the exon-junction complex core component MLN51. We employed exon arrays for this analysis, as this platform detects expression levels of individual exons and thus allows detection of not only differentially expressed transcripts (DETs), but also alternative isoform transcripts (AITs). The latter is particularly relevant to our study because alternative RNA processing events (e.g., RNA splicing, alternative promoter usage, and alternative polyadenylation-site usage) often place a translation termination codon in a premature context and thereby trigger NMD. Compare different expressed genes and transcript isoforms in mouse NSCs miR-128 positive vs miR-128 negative (Control). Mouse NSCs, that do not normally express miR-128, were nucleofected with either miR-128 (biological triplicates were analysed) or miR-Control (biological triplicates). RNA was extracted 72hrs later, and Exon Array was performed to identify target genes.

2011-04-28 | E-GEOD-28889 | biostudies-arrayexpress

Nonsense-mediated decay of alternative precursor mRNA splicing variants is a major determinant of the eukaryotic steady state transcriptome

Project description:Nonsense-mediated mRNA decay (NMD) is a eukaryotic surveillance pathway that recognizes aberrant transcripts arising from mutations and transcriptional mistakes. Moreover, differential transcript processing such as alternative precursor mRNA splicing (AS) can generate NMD substrates, however, the extent of coupled AS and NMD remained unclear. To investigate NMD targeting of AS variants, we performed transcriptome-wide splicing studies using Arabidopsis thaliana single and double mutants in the NMD factor homologues UPF1 and UPF3, as well as samples treated with the translation inhibitor cycloheximide (CHX). Our analyses revealed that at least 17.5% of all multi-exon, protein-coding genes produce splicing variants of all major types that are targeted by NMD, with a significant fraction originating from the splicing of cryptic introns. Furthermore, accumulation of many intron-retained mRNAs in the mutants, but not in response to CHX suggests the action of distinct routes of NMD with variable impact of translation. Importantly, 92.3% of the NMD-responsive mRNAs exhibit classical NMD-eliciting features, supporting their authenticity as direct targets. NMD-dependent AS variants are linked to diverse biological functions, including the poison exon-mediated regulation of signaling and posttranslational protein modification components. In addition to mRNAs, numerous non-coding RNAs as well as newly identified transcripts derived from intergenic regions were shown to be NMD responsive. In summary, our comprehensive analysis of AS-coupled NMD provides strong evidence for a major function of this pathway in shaping the transcriptome, having fundamental implications in gene regulation and quality control of transcript processing steps in higher eukaryotes. Comparison of gene expression and alternative splicing patterns in control and nonsense-mediated decay (NMD)-impaired Arabidopsis seedlings

2013-10-01 | E-GEOD-41432 | biostudies-arrayexpress

Nonsense-mediated mRNA decay in Tetrahymena is EJC independent and requires a protozoa-specific nuclease

Project description:Nonsense-mediated mRNA decay (NMD) is essential for removing premature termination codon (PTC)-containing transcripts from cells. Studying the NMD pathway in model organisms can help to elucidate the NMD mechanism of humans and improves our understanding of how this biologically important process has evolved. Protozoa are among the earliest branching eukaryotes. Their NMD mechanism is poorly understood and may be primordial. We demonstrate that highly conserved Upf proteins (Upf1a, Upf2, and Upf3) are involved in the NMD pathway of the ciliate, Tetrahymena thermophila. We further show that a novel protozoa-specific nuclease, Smg6L, is responsible for destroying many NMD-targeted transcripts. The transcriptome-wide identification and characterization of NMD-targeted transcripts in vegetative Tetrahymena cells showed that many have exon–exon junctions downstream of the termination codon. However, Tetrahymena homologs of exon junction complex (EJC) core components do not form a complex and are dispensable for NMD, suggesting that NMD is EJC independent in this early branching eukaryote.

2017-07-17 | GSE90899 | GEO

Broad existence of pluripotent factor regulated transcript isoforms with stage-specific alternative first exon (SAFE) in mouse embryonic stem cells

Project description:Alternative first exon isoforms are frequently observed among transcriptomes derived from different developmental stages of eukaryotes. Stage-specific alternative first exon (SAFE) transcripts are usually involved in the regulation of cell development in spatiotemporal manners. The transcriptome analysis for RNA-seq data make it possible to identify specifically used first exons in mouse embryonic stem cells (mESCs) compared to somatic cells, just like tail tip fibroblasts (TTFs). In this study, we identify 128 genes producing SAFE isoforms in mESCs.

2015-10-01 | GSE56529 | GEO

Expression changes in the absence of miR-128 in striatal D1-receptor positive neurons

Project description:MicroRNA regulates protein expression of cells by repressing translation of specific target messenger transcripts. Loss of the neuron specific microRNA miR-128 in Dopamine D1-receptor expressing neurons in the murine striatum (D1-MSNs) lead to increased neuronal excitability, locomotor hyperactivity and fatal epilepsy. To examine expression changes in the absence of miR-128 in D1-MSNs, we used mice expressing EGFP-tagged ribosomes in D1-MSNs with either D1-MSN-specific homozygous deletion of miR-128-2 locus or no deletion. Transcripts co-immunoprecipitated with tagged ribosomes were analyzed by microarray.

2014-01-07 | GSE48813 | GEO

Expression changes in the absence of miR-128 in striatal D1-receptor positive neurons

2014-01-07 | E-GEOD-48813 | biostudies-arrayexpress

Nonsense-mediated decay of alternative precursor mRNA splicing variants is a major determinant of the eukaryotic steady state transcriptome

2013-10-01 | GSE41432 | GEO

Nanopore sequencing reveals endogenous NMD-targeted isoforms in human cells

Project description:Nonsense-mediated mRNA decay (NMD) is a eukaryotic, translation-dependent degradation pathway that targets mRNAs with premature termination codons and also regulates the expression of some mRNAs that encode full-length proteins. Although many genes express NMD-sensitive transcripts, identifying them based on short-read sequencing data remains a challenge. To identify and analyze endogenous targets of NMD, we applied cDNA Nanopore sequencing and short-read sequencing to human cells with varying expression levels of NMD factors. Our approach detects full-length NMD substrates that are highly unstable and increase in levels or even only appear when NMD is inhibited. Among the many new NMD-targeted isoforms that our analysis identified, most derive from alternative exon usage. The isoform-aware analysis revealed many genes with significant changes in splicing but no significant changes in overall expression levels upon NMD knockdown. NMD-sensitive mRNAs have more exons in the 3΄UTR and for mRNAs with a termination codon in the last exon. The length of the 3΄UTR per se does not correlate with NMD sensitivity. Analysis of splicing signals reveals isoforms where NMD has been co-opted in the regulation of gene expression, but a main function is most likely to rid the transcriptome of isoforms resulting from spurious splicing events. Long-read sequencing enabled the identification of many novel NMD-sensitive mRNAs and revealed both known and unexpected features concerning their biogenesis and their biological role. Our data provide a highly valuable resource of human NMD transcript targets for future genomic and transcriptomic applications.

2021-07-20 | E-MTAB-10452 | biostudies-arrayexpress

Regulation of alternative splicing by the core spliceosomal machinery

Project description:Abstract: Alternative splicing (AS) plays a major role in the generation of proteomic diversity and in gene regulation. However, the role of the basal splicing machinery in regulating AS remains poorly understood. Here we show that the core snRNP protein SmB/B’ self-regulates its expression by promoting the inclusion of a highly-conserved alternative exon in its own pre-mRNA that targets the spliced transcript for nonsense-mediated mRNA decay (NMD). Depletion of SmB/B’ in human cells results in reduced levels of snRNPs and in a striking reduction in the inclusion levels of hundreds of alternative exons, with comparatively few effects on constitutive exon splicing levels. The affected alternative exons are enriched in genes encoding RNA processing and other RNA binding factors, and a subset of these exons also regulate gene expression by activating NMD. Our results thus demonstrate a role for the core spliceosomal machinery in controlling an exon network that appears to modulate the levels of many RNA processing factors.

2011-02-01 | GSE26463 | GEO

Striatal gene expression profile of the YAC 128 mouse

Project description:The Yeast Artificial Chomosome (YAC) 128 model of Huntington's disease shows substantial deficits in motor, learning and memory tasks and alterations in its transcriptional profile. We examined the changes in the transcriptional profile in the YAC 128 mouse model of HD at 6, 12, and 18 weeks

2016-07-07 | GSE70656 | GEO

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