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The Poly(C) binding protein Pcbp2, and its retrotransposed derivative Pcbp1, are independently essential to mouse development

ABSTRACT: RNA-binding proteins participate in a complex array of post-transcriptional controls essential to cell-type specification and somatic development. Despite their detailed biochemical characterizations, the degree to which each RNA-binding protein impacts on mammalian embryonic development remains incompletely defined and the level of functional redundancy among subsets of these proteins remains open to question. The poly-(C) binding proteins, Pcbp’s (aCPs, hnRNPEs), are encoded by a highly conserved and broadly expressed gene family. The two major Pcbp isoforms, Pcbp2 and Pcbp1, are robustly expressed in a wide range of tissues and exert both nuclear and cytoplasmic controls over gene expression. Here we report that Pcbp1-null embryos are rendered nonviable in the peri-implantation stage. In contrast, Pcbp2-null embryos survive until mid-gestation at which time they undergo a loss in viability associated with cardiovascular and hematopoietic abnormalities. Adult mice heterozygous for either Pcbp1 or Pcbp2 null alleles display a mild and non-disruptive growth defect. These data reveal that Pcbp1 and Pcbp2 are individually essential for mouse embryonic development and post-natal growth, reveal a non-redundant in vivo role for Pcpb2 in hematopoiesis, and provide direct evidence that Pcbp1, a retrotransposed derivative of Pcpb2, has evolved essential function(s) in the mammalian genome.

ORGANISM(S): Mus musculus

PROVIDER: GSE72491 | GEO | 2015/11/05

SECONDARY ACCESSION(S): PRJNA294156

REPOSITORIES: GEO

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The Poly(C) binding protein Pcbp2, and its retrotransposed derivative Pcbp1, are independently essential to mouse development

Project description:RNA-binding proteins participate in a complex array of post-transcriptional controls essential to cell-type specification and somatic development. Despite their detailed biochemical characterizations, the degree to which each RNA-binding protein impacts on mammalian embryonic development remains incompletely defined and the level of functional redundancy among subsets of these proteins remains open to question. The poly-(C) binding proteins, Pcbp's (aCPs, hnRNPEs), are encoded by a highly conserved and broadly expressed gene family. The two major Pcbp isoforms, Pcbp2 and Pcbp1, are robustly expressed in a wide range of tissues and exert both nuclear and cytoplasmic controls over gene expression. Here we report that Pcbp1-null embryos are rendered nonviable in the peri-implantation stage. In contrast, Pcbp2-null embryos survive until mid-gestation at which time they undergo a loss in viability associated with cardiovascular and hematopoietic abnormalities. Adult mice heterozygous for either Pcbp1 or Pcbp2 null alleles display a mild and non-disruptive growth defect. These data reveal that Pcbp1 and Pcbp2 are individually essential for mouse embryonic development and post-natal growth, reveal a non-redundant in vivo role for Pcpb2 in hematopoiesis, and provide direct evidence that Pcbp1, a retrotransposed derivative of Pcpb2, has evolved essential function(s) in the mammalian genome. mRNA-seq on fetal liver tissue from 12.5 days post coitum. 4 replicates of WT and 3 replicates of PCBP2 Knockout

2015-11-05 | E-GEOD-72491 | biostudies-arrayexpress

Next Generation Sequencing to determine the roles of RNA-binding proteins PCBP1 and PCBP2 on murine erythropoiesis

Project description:E14.5 fetal liver cells from CD-1 mice were enriched for hematopoietic progenitors. The purified hematopoietic progenitor cells were infected immediately with retroviruses encoding shRNAs that target Pcbp1, Pcbp2, as well as two sets of control shRNAs; Luciferase and scrambled sequence. The transduced cells were grown for 48 hours. These cells were collected (‘Day 0’ cells), or washed and resuspended in differentiation medium and incubated for an additional 2 days (‘Day 2’ cells). 1ug of total RNA isolated from ‘Day 0’ and ‘Day 2’ cells from each Pcbp1 or Pcbp2 depleted sample was used for cDNA library construction after polyA selection. A total of 9 samples were generated from each of the two time points: 3 controls; Pcbp1 knockdowns with three distinctly targeting shRNAs (sh1,3,4); Pcbp2 knockdown with three distinctly targeting shRNAs (sh1,3,4). Sequencing was carried out using a 150nt paired-end sequencing protocol.

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The Poly(C)-binding protein Pcbp2 is essential for CD4+ T cell development and proliferation.

Project description:Defining the molecular mechanisms that impact T cell maturation and function is important because abnormalities in these processes can lead to immunodeficient states or autoimmunity. RNA-binding proteins (RBPs) have emerged as critical factors in thymopoiesis, immune cell lineage commitment and maintenance, and as modulators of immune responses. The RBP paralogs Pcbp1 and Pcbp2 are widely expressed in the innate and adaptive immune systems and are each essential for mouse development. Pcbp1 has been shown to prevent conversion of CD4+ effector T cells into Foxp3+ regulatory T cells (Treg), with loss of Pcbp1 resulting in increased Treg differentiation. To determine whether Pcbp2 also is required for CD4+ T cell development and function, we derived mice with conditional Pcbp2 deletion in CD4+ T cells and assessed their overall phenotype and proliferative responses to activating stimuli. We found that Pcbp2 is essential for CD4+ T conventional cell (Tconv) proliferation, working through regulation of CD4 receptor co-stimulatory signaling. In addition, our data demonstrate a clear association between Pcbp2 control of Runx1 exon 6 splicing in CD4+ T cells and a specific role for Pcbp2 in the maintenance of peripheral CD4+ lymphocyte population size. Pcbp2 deficiency in the CD4+ lineage did not impact Treg abundance in vivo or function in vitro. Last, we show that Pcbp2 function is required for optimal in vivo Tconv cell activation in a T cell adoptive transfer colitis model system. These data lead us to conclude that Pcbp2 is a critical regulator of T cell signaling and function in the CD4+ lineage.

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Next Generation Sequencing to determine the roles of RNA-binding proteins PCBP1 and PCBP2 on murine erythropoiesis

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Project description:RIP-Chip analysis of PCBP2 and identification of preferentially associated mRNAs. T98G cells were transfected transiently with BAP-tagged constructs. BAP-tagged proteins were biotinylated in vivo by the co-transfected hBirA enzyme. RNPs were recovered via precipitation with Steptavidin-sepharose beads. Finally, RNAs were purified and analyzed on microarrays. BAP-GFP as control was used in three independent sets of experiments. Two-condition experiment, BAP-PCBP2 vs. BAP-GFP cells. Biological replicates: 3 BAP-PCBP2 replicates, 3 BAP-GFP (Control) replicates

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Transcriptome targets of PCBP1 in T cells

Project description:Iron deposition is frequently observed in human autoinflammatory diseases, such as in the brain of patients with multiple sclerosis or in the synovial fluid of patients with rheumatoid arthritis1-5. Yet, the functional outcome of excessive iron in inflammatory conditions is largely unknown. Granulocyte macrophage colony-stimulating factor (GM-CSF) is a proinflammatory cytokine promoting myeloid cell maturation and activation6 and is essential for the pathogenesis of many autoimmune diseases, including autoimmune encephalomyelitis7-10. Post-transcriptional regulation of GM-CSF is mediated primarily through its 3’ untranslated region (3’UTR) via interaction with specific RNA-binding proteins11. Here we show that a RNA-binding protein PCBP1 senses intracellular iron and post-transcriptionally promotes GM-CSF production. In a short hairpin (sh) RNA screening, we found that Poly(rC) binding protein 1 (PCBP1) enhanced GM-CSF 3’UTR activity and its endogenous mRNA stability. PCBP1 deficiency in autoreactive T cells resulted in a compromised production of GM-CSF and other proinflammatory cytokines, abolishing their capacity in inducing experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Using Crosslinking and Immunoprecipitation (CLIP)12, we demonstrated that PCBP1 promoted mRNA stability by recognizing CU rich elements in the 3’UTRs of pro-inflammatory cytokines. Furthermore, iron depletion induced rapid caspase-mediated proteolysis of PCBP1 and inhibited the production of GM-CSF and a module of 24 cytokines in primary murine and human T cells. Our study thus demonstrates that PCBP1 is critical for the post-transcriptional regulation of proinflammatory cytokines, and indicates that sensing iron may represent a simple yet effective means to adjust the inflammatory response to tissue homeostatic alterations.

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RNA binding protein Pcbp1 maintains mitochondria integrity to promote antibody production and germinal center response[scRNA-seq]

Project description:B cells are crucial for adaptive immunity, orchestrating humoral responses by producing antibodies essential for pathogen clearance. Here, we show that Poly(rC) binding protein 1 (Pcbp1), a multifunctional RNA-binding protein, is a key regulator of antibody production in B cells. Pcbp1 deficiency in B cells resulted in significant reductions in IgM expression at steady state and compromised differentiation of germinal center B cells and production of high-affinity antibodies upon immunization. These effects result from compromised mitochondrial integrity in Pcbp1-deficient B cells, including compromised mitochondrial electron transport chain (ETC) complex I and increased mitochondrial ROS production. Blocking mitochondrial ROS production rescued IgM production and improved germinal center responses caused by Pcbp1 deficiency. Mechanistically, Pcbp1 promotes the expression of Fdxr, a critical component of ETC complex I, via binding to its 3’UTR. Overall, our findings reveal a novel role for Pcbp1 in regulating mitochondrial function, protein synthesis, and antibody responses in B cells, providing novel insight into post-transcriptional regulation and mitochondrial functions.

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RNA binding protein Pcbp1 maintains mitochondria integrity to promote antibody production and germinal center response[RNA-seq]

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