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An evolutionarily conserved function of the pre-mRNA splicing regulator TNPO3 for T cell development

ABSTRACT: All vertebrates possess lymphocytes, enabling the functional interrogation of this evolutionarily conserved organizing principle of adaptive immunity in non-mammalian species. A forward genetic screen in zebrafish indicated that a mutation of tnpo3, encoding a regulator of alternative splicing of pre-mRNAs, specifically impaired intrathymic T cell development. In mouse T cells, Tnpo3 deficiency predominantly disrupted the splicing of genes encoding RNA-binding motifs, and it specifically blocked the splicing of Va11, associated with reduced numbers of peripheral T cells and the complete loss of iNKT cells. Our results reveal an evolutionarily conserved function of a pre-mRNA processing factor for T cell development, uncovering a previously unappreciated checkpoint during the formation of mature mRNAs of the Tcra gene.

ORGANISM(S): Mus musculus Danio rerio

PROVIDER: GSE77137 | GEO | 2019/01/23

REPOSITORIES: GEO

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Forward genetic screens in zebrafish identify novel molecular pathways regulating early T cell development

Project description:Lymphocytes represent basic components of vertebrate adaptive immune systems, suggesting the utility of non-mammalian models to define the molecular basis of their development and differentiation. Our forward genetic screens in zebrafish for recessive mutations affecting early T cell development revealed several major genetic pathways. The identification of lineage-specific transcription factors and specific components of cytokine signaling and DNA replication/repair pathways known from studies of immuno-compromised mammals provided an evolutionary cross-validation of the screen design. Unexpectedly, however, certain pre-mRNA processing factor genes, including tnpo3, encoding a regulator of alternative splicing, were also found to play a specific role in early T cell development. In both zebrafish and mouse, TNPO3 deficiency impairs intrathymic T cell differentiation, illustrating evolutionarily conserved and cell type-specific functions of certain pre-mRNA processing factor.

2016-11-28 | GSE77480 | GEO

An evolutionarily conserved function of the pre-mRNA splicing regulator TNPO3 for T cell development

Project description:An evolutionarily conserved function of the pre-mRNA splicing regulator TNPO3 for T cell development

| PRJNA309534 | ENA

Homo sapiens

Project description:Son Maintains Accurate Splicing of Pre-mRNAs Encoding Chromatin Modifiers

| PRJNA138951 | ENA

THUMPD2 catalyzes N2-methylation on the spliceosome catalytic center of U6 snRNA and regulates pre-mRNA splicing and retina degeneration

Project description:How the relatively evolutionarily conserved spliceosome is able to manage the enormously expanded number of splicing events that occur in humans (~200,000 vs. ~400 reported for yeast) is not well understood. Here, we show deposition of one RNA modification-N2-methylguanosine (m2G)-on the G72 nucleoside of U6 snRNA (known to function as the catalytic center of the spliceosome) results in profoundly increased pre-mRNA splicing activity in human cells. This U6 m2G72 modification is conserved among vertebrates. Further, we demonstrate that THUMPD2 is the methyltransferase responsible for U6 m2G72 and show that it interacts with an auxiliary protein (TRMT112) to specifically recognize both sequence and structural elements of U6. THUMPD2 KO blocks U6 m2G72 and down-regulates the pre-mRNA splicing activity of major spliceosome, yielding thousands of changed alternative splicing events of endogenous pre-mRNAs. Notably, the aberrantly spliced pre-mRNA population of the THUMPD2 KO cells elicits the nonsense-mediated mRNA decay (NMD) pathway and restricts cell proliferation. We also show that THUMPD2-mediated control of the U6 m2G72 modification is associated with age-related macular degeneration and retinal function. Our study thus demonstrates how an RNA epigenetic modification of the major spliceosome differentially regulates global mRNA splicing and impacts physiology and disease.

2024-01-02 | GSE236689 | GEO

The fission yeast MTREC complex targets CUTs and unspliced mRNAs to the nuclear exosome

Project description:Cryptic unstable transcripts (CUTs) are rapidly degraded by the nuclear exosome. However, the mechanism by which they are recognized and targeted to the exosome is not fully understood. Here, we report that the MTREC complex, which has recently been shown to promote degradation of meiotic mRNAs and regulatory ncRNAs, is also the major nuclear exosome targeting complex for CUTs and unspliced pre-mRNAs in Schizosaccharomyces pombe. MTREC complex specifically binds to CUTs, meiotic mRNAs and unspliced pre-mRNA transcripts and targets these RNAs for degradation by the nuclear exosome, while the TRAMP complex has only a minor role in this process. The MTREC complex physically interacts with the nuclear exosome and with various RNA-binding and -processing complexes, coupling RNA processing to the RNA degradation machinery. Our study reveals the central role of the evolutionarily conserved MTREC complex in RNA quality control, and in the recognition and elimination of CUTs.

2015-04-22 | PXD001908 | Pride

Transcript Specificity in Yeast Pre-mRNA Splicing Revealed by Mutations in Core Spliceosomal Components

Project description:Appropriate expression of most eukaryotic genes requires the removal of introns from their pre-messenger RNAs (pre-mRNAs), a process catalyzed by the spliceosome. In higher eukaryotes a large family of auxiliary factors known as SR proteins can improve the splicing efficiency of transcripts containing suboptimal splice sites by interacting with distinct sequences present in those pre-mRNAs. The yeast Saccharomyces cerevisiae lacks functional equivalents of most of these factors; thus, it has been unclear whether the spliceosome could effectively distinguish among transcripts. To address this question, we have used a microarray-based approach to examine the effects of mutations in 18 highly conserved core components of the spliceosomal machinery. The kinetic profiles reveal clear differences in the splicing defects of particular pre-mRNA substrates. Most notably, the behaviors of ribosomal protein gene transcripts are generally distinct from other intron-containing transcripts in response to several spliceosomal mutations. However, dramatically different behaviors can be seen for some pairs of transcripts encoding ribosomal protein gene paralogs, suggesting that the spliceosome can readily distinguish between otherwise highly similar pre-mRNAs. The ability of the spliceosome to distinguish among its different substrates may therefore offer an important opportunity for yeast to regulate gene expression in a transcript-dependent fashion. Given the high level of conservation of core spliceosomal components across eukaryotes, we expect that these results will significantly impact our understanding of how regulated splicing is controlled in higher eukaryotes as well. Keywords: time course, splicing mutant, splicing-specific microarray

2007-04-04 | GSE7419 | GEO

Alternative splicing controls Leucine-rich repeat domain modularity in NOD-like receptors

Project description:Leucine-rich repeat (LRR) domains are evolutionarily conserved in proteins that function in development and immunity. Somatic recombination of LRR sequences evolved to create diversity in jawless vertebrate adaptive immunity, yet the role repetitive LRR-encoding exons in humans remains unknown. We performed this RNA Seq study to understand how alternative splicing of NOD-like receptors (NLRs) at the locus encoding a LRR domain can regulate NLRs function, with a focus on NLRP3.

2019-06-09 | GSE117206 | GEO

SNW1 is required for sister chromatid cohesion

Project description:Although splicing is essential for the expression of most eukaryotic genes, inactivation of splicing factors causes specific defects in mitosis. The molecular cause of this defect is unknown. Here we show that the spliceosome subunits SNW1 and PRPF8 are essential for sister chromatid cohesion in human cells. A transcriptome-wide analysis revealed that SNW1 or PRPF8 depletion affects the splicing of specific introns in a subset of pre-mRNAs, including pre-mRNAs encoding the cohesion protein sororin and the APC/C subunit APC2. SNW1 depletion causes cohesion defects predominantly by reducing sororin levels, which causes destabilisation of cohesin on DNA. SNW1 depletion also reduces APC/C activity and contributes to cohesion defects indirectly by delaying mitosis and causing ‘cohesion fatigue’. Simultaneous expression of sororin and APC2 from intron-less cDNAs restores cohesion in SNW1 depleted cells. These results indicate that the spliceosome is required for mitosis because it enables expression of genes essential for cohesion. Our transcriptome-wide identification of retained introns in SNW1 and PRPF8 depleted cells may help to understand the aetiology of diseases associated with splicing defects, such as retinosa pigmentosum and cancer.

2016-06-29 | PXD001249 | Pride

SNW1 is required for sister chromatid cohesion

2017-04-02 | MSV000080878 | MassIVE

Arabidopsis RBV is a conserved WD40 repeat protein that promotes microRNA biogenesis and ARGONAUTE1 loading[RNA-seq]

Project description:MicroRNAs (miRNAs) play crucial roles in gene expression regulation through RNA cleavage or translation repression. Here, we report the identification of an evolutionarily conserved WD40 domain protein as a player in miRNA biogenesis in Arabidopsis thaliana. A mutation in the REDUCTION IN BLEACHED VEIN AREA (RBV) gene encoding a WD40 domain protein led to the suppression of leaf bleaching caused by an artificial miRNA; the mutation also led to a global reduction in the accumulation of endogenous miRNAs. The nuclear protein RBV promotes the transcription of MIR genes into pri-miRNAs by enhancing the occupancy of RNA polymerase II (Pol II) at MIR gene promoters. RBV also promotes the loading of miRNAs into AGO1. In addition, RNA-seq revealed a global splicing defect in the mutant. Thus, this evolutionarily conserved, nuclear WD40 domain protein acts in miRNA biogenesis and RNA splicing.

2022-02-26 | GSE152910 | GEO

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