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Omics score: 1000

Transcriptome profiling of blood cells from Nxf1 mutant and control mice

ABSTRACT: Transcriptome profiling of blood cells from Nxf1 mutant and control mice

PROVIDER: PRJNA592451 | ENA |

REPOSITORIES: ENA

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Germline heterozygous mutations in Nxf1 perturb RNA metabolism and trigger thrombocytopenia and lymphopenia in mice.

Chappaz Stéphane S Law Charity W CW Dowling Mark R MR Carey Kirstyn T KT Lane Rachael M RM Ngo Linh H LH Wickramasinghe Vihandha O VO Smyth Gordon K GK Ritchie Matthew E ME Kile Benjamin T BT

Blood advances 20200401 7

In eukaryotic cells, messenger RNA (mRNA) molecules are exported from the nucleus to the cytoplasm, where they are translated. The highly conserved protein nuclear RNA export factor1 (Nxf1) is an important mediator of this process. Although studies in yeast and in human cell lines have shed light on the biochemical mechanisms of Nxf1 function, its contribution to mammalian physiology is less clear. Several groups have identified recurrent NXF1 mutations in chronic lymphocytic leukemia (CLL), pla ...[more]

PMID: 32236527

Similar Datasets

Transcriptome profiling of purified red blood cells from Nxf1 mutant and control mice [Erythrocytes]

2020-03-04 | GSE141160 | GEO

Transcriptome profiling of purified red blood cells from Nxf1 mutant and control mice [Erythrocytes]

Project description:Transcriptome profiling of purified red blood cells from Nxf1 mutant and control mice [Erythrocytes]

| PRJNA592453 | ENA

Transcriptome profiling of purified mouse platelets from Nxf1 mutant and control mice [Platelet]

Project description:Purpose: Nxf1 is thought to be an essential nuclear exporter of messenger RNA (mRNA) in eukaryotic cells. Whether perturbations in the Nxf1 pathway affect mammalian physiology is not known. The aim of this study is to determine the impact of a Nxf1 mutation in the representation of mRNA transcripts in platelets. Methods: Platelets were purified from individual males. Blood was obtained by cardiac puncture into 0.1 volume of Aster Jandl citrate-based anticoagulant. Mouse platelet rich fraction was obtained by centrifugation of the murine blood at 125 g for 8 min at room temperature, followed by centrifugation of the supernatant buffy coat at 125 g for 8 min. Mouse platelets were washed by two sequential centrifugations at 860 g for 5 min in 140 mM NaCl, 5 mM KCl, 12 mM trisodium citrate, 10 mM glucose, and 12.5 mM sucrose, pH 6.0.The platelet pellet was resuspended in 10 mM Hepes, 140 Mm NaCl, 3 mM KCl, 0.5 mM MgCl2, 10 mM glucose, and 0.5 mM NaHCO3, pH 7.4. The purity of each platelet suspension was assessed by flow cytometry and suspensions for which more than 98% of total events were CD41+ platelets were pooled together. RNA was purified with Norgen cytoplasmic and nuclear fractionation RNA purification kit. Overall design: Platelets were purified from individual Nxf1 mutant males (littermate controls are available from GEO accession GSE75896). The purity of each suspension was assessed by flow cytometry. Suspensions of identical genotype for which more than 98% of total events were CD41+ platelets were pooled together. Pooled platelet preparations from mutant (this study) and wild-type littermate controls (GSE75896) were prepared on 3 distinct days. The GSM4196370-GSM4196372 sample records are duplicated sample records of GSM1969530-GSM1969532 (in GSE75896) for the convenient retrieval of the complete raw data from SRA.

2020-03-04 | GSE141159 | GEO

Germline heterozygous mutations in Nxf1 perturb RNA metabolism and trigger thrombocytopenia and lymphopenia in mice.

Project description:In eukaryotic cells, messenger RNA (mRNA) molecules are exported from the nucleus to the cytoplasm, where they are translated. The highly conserved protein nuclear RNA export factor1 (Nxf1) is an important mediator of this process. Although studies in yeast and in human cell lines have shed light on the biochemical mechanisms of Nxf1 function, its contribution to mammalian physiology is less clear. Several groups have identified recurrent NXF1 mutations in chronic lymphocytic leukemia (CLL), placing it alongside several RNA-metabolism factors (including SF3B1, XPO, RPS15) whose dysregulation is thought to contribute to CLL pathogenesis. We report here an allelic series of germline point mutations in murine Nxf1. Mice heterozygous for these loss-of-function Nxf1 mutations exhibit thrombocytopenia and lymphopenia, together with milder hematological defects. This is primarily caused by cell-intrinsic defects in the survival of platelets and peripheral lymphocytes, which are sensitized to intrinsic apoptosis. In contrast, Nxf1 mutations have almost no effect on red blood cell homeostasis. Comparative transcriptome analysis of platelets, lymphocytes, and erythrocytes from Nxf1-mutant mice shows that, in response to impaired Nxf1 function, the cytoplasmic representation of transcripts encoding regulators of RNA metabolism is altered in a unique, lineage-specific way. Thus, blood cell lineages exhibit differential requirements for Nxf1-mediated global mRNA export.

| S-EPMC7160253 | BioStudies

Transcriptome profiling of cytoplasmic fraction of naïve CD8 T cells from Nxf1 mutant and control mice [Lymphocytes]

2020-03-04 | GSE141158 | GEO

Transcriptome profiling of purified mouse platelets from Nxf1 mutant and control mice [Platelet]

Project description:Transcriptome profiling of purified mouse platelets from Nxf1 mutant and control mice [Platelet]

| PRJNA592454 | ENA

Transcriptome profiling of cytoplasmic fraction of naïve CD8 T cells from Nxf1 mutant and control mice [Lymphocytes]

Project description:Transcriptome profiling of cytoplasmic fraction of naïve CD8 T cells from Nxf1 mutant and control mice [Lymphocytes]

| PRJNA592455 | ENA

Multipotent genetic suppression of retrotransposon-induced mutations by Nxf1 through fine-tuning of alternative splicing.

Project description:Cellular gene expression machinery has coevolved with molecular parasites, such as viruses and transposons, which rely on host cells for their expression and reproduction. We previously reported that a wild-derived allele of mouse Nxf1 (Tap), a key component of the host mRNA nuclear export machinery, suppresses two endogenous retrovirus-induced mutations and shows suggestive evidence of positive selection. Here we show that Nxf1(CAST) suppresses a specific and frequent class of intracisternal A particle (IAP)-induced mutations, including Ap3d1(mh2J), a model for Hermansky-Pudlak syndrome, and Atcay(hes), an orthologous gene model for Cayman ataxia, among others. The molecular phenotype of suppression includes approximately two-fold increase in the level of correctly-spliced mRNA and a decrease in mutant-specific, alternatively-processed RNA accumulating from the inserted allele. Insertional mutations involving ETn and LINE elements are not suppressed, demonstrating a high degree of specificity to this suppression mechanism. These results implicate Nxf1 in some instances of pre-mRNA processing, demonstrate the useful range of Nxf1(CAST) alleles for manipulating existing mouse models of disease, and specifically imply a low functional threshold for therapeutic benefit in Cayman ataxia.

| S-EPMC2674570 | BioStudies

Evolutionary development of redundant nuclear localization signals in the mRNA export factor NXF1.

Project description:In human cells, the mRNA export factor NXF1 resides in the nucleoplasm and at nuclear pore complexes. Karyopherin ?2 or transportin recognizes a proline-tyrosine nuclear localization signal (PY-NLS) in the N-terminal tail of NXF1 and imports it into the nucleus. Here biochemical and cellular studies to understand the energetic organization of the NXF1 PY-NLS reveal unexpected redundancy in the nuclear import pathways used by NXF1. Human NXF1 can be imported via importin ?, karyopherin ?2, importin 4, importin 11, and importin ?. Two NLS epitopes within the N-terminal tail, an N-terminal basic segment and a C-terminal R-X(2-5)-P-Y motif, provide the majority of binding energy for all five karyopherins. Mutation of both NLS epitopes abolishes binding to the karyopherins, mislocalized NXF1 to the cytoplasm, and significantly compromised its mRNA export function. The understanding of how different karyopherins recognize human NXF1, the examination of NXF1 sequences from divergent eukaryotes, and the interactions of NXF1 homologues with various karyopherins reveals the evolutionary development of redundant NLSs in NXF1 of higher eukaryotes. Redundancy of nuclear import pathways for NXF1 increases progressively from fungi to nematodes and insects to chordates, potentially paralleling the increasing complexity in mRNA export regulation and the evolution of new nuclear functions for NXF1.

| S-EPMC3226482 | BioStudies

TREX exposes the RNA-binding domain of Nxf1 to enable mRNA export.

Project description:The metazoan TREX complex is recruited to mRNA during nuclear RNA processing and functions in exporting mRNA to the cytoplasm. Nxf1 is an mRNA export receptor, which binds processed mRNA and transports it through the nuclear pore complex. At present, the relationship between TREX and Nxf1 is not understood. Here we show that Nxf1 uses an intramolecular interaction to inhibit its own RNA-binding activity. When the TREX subunits Aly and Thoc5 make contact with Nxf1, Nxf1 is driven into an open conformation, exposing its RNA-binding domain, allowing RNA binding. Moreover, the combined knockdown of Aly and Thoc5 markedly reduces the amount of Nxf1 bound to mRNA in vivo and also causes a severe mRNA export block. Together, our data indicate that TREX provides a license for mRNA export by driving Nxf1 into a conformation capable of binding mRNA.

| S-EPMC3654228 | BioStudies

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