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THOC5, a member of the mRNA export complex, contributes to processing of a subset of wingless/integrated (Wnt) target mRNAs and integrity of the gut epithelial barrier.

ABSTRACT: BACKGROUND: THO (Suppressors of the transcriptional defects of hpr1 delta by overexpression) complex 5 (THOC5), an mRNA export protein, is involved in the expression of only 1% of all genes. Using an interferon inducible knockout mouse system, we have previously shown that THOC5 is an essential element in the maintenance of hematopoietic stem cells and cytokine-mediated hematopoiesis in adult mice. Here we interrogate THOC5 function in cell differentiation beyond the hematopoietic system and study pathological changes caused by THOC5 deficiency. RESULTS: To examine whether THOC5 plays a role in general differentiation processes, we generated tamoxifen inducible THOC5 knockout mice. We show here that the depletion of THOC5 impaired not only hematopoietic differentiation, but also differentiation and self renewal of the gut epithelium. Depletion of the THOC5 gene did not cause pathological alterations in liver or kidney. We further show that THOC5 is indispensable for processing of mRNAs induced by Wnt (wingless/integrated) signaling which play key roles in epithelial cell differentiation/proliferation. A subset of Wnt target mRNAs, SRY-box containing gene 9 (Sox9), and achaete-scute complex homolog 2 (Ascl2), but not Fibronectin 1 (Fn1), were down-regulated in THOC5 knockout intestinal cells. The down-regulated Wnt target mRNAs were able to bind to THOC5. Furthermore, pathological alterations in the gastrointestinal tract induced translocation of intestinal bacteria and caused sepsis in mice. The bacteria translocation may cause Toll-like receptor activation. We identified one of the Toll-like receptor inducible genes, prostaglandin-endoperoxidase synthase 2 (Ptgs2 or COX2) transcript as THOC5 target mRNA. CONCLUSION: THOC5 is indispensable for processing of only a subset of mRNAs, but plays a key role in processing of mRNAs inducible by Wnt signals. Furthermore, THOC5 is dispensable for general mRNA export in terminally differentiated organs, indicating that multiple mRNA export pathways exist. These data imply that THOC5 may be a useful tool for studying intestinal stem cells, for modifying the differentiation processes and for cancer therapy.

SUBMITTER: Saran S

PROVIDER: S-EPMC4222586 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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THOC5, a member of the mRNA export complex, contributes to processing of a subset of wingless/integrated (Wnt) target mRNAs and integrity of the gut epithelial barrier.

Saran Shashank S Tran Doan D H DD Klebba-Färber Sabine S Moran-Losada Patricia P Wiehlmann Lutz L Koch Alexandra A Chopra Himpriya H Pabst Oliver O Hoffmann Andrea A Klopfleisch Robert R Tamura Teruko T

BMC cell biology 20131122

<h4>Background</h4>THO (Suppressors of the transcriptional defects of hpr1 delta by overexpression) complex 5 (THOC5), an mRNA export protein, is involved in the expression of only 1% of all genes. Using an interferon inducible knockout mouse system, we have previously shown that THOC5 is an essential element in the maintenance of hematopoietic stem cells and cytokine-mediated hematopoiesis in adult mice. Here we interrogate THOC5 function in cell differentiation beyond the hematopoietic system ...[more]

PMID: 24267292

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Project description:Cell growth, differentiation, and commitment to a restricted lineage are guided by a timely expressed set of growth factor/cytokine receptors and their down-stream transcription factor genes. Transcriptional control mechanisms of gene expression during differentiation have been mainly studied by focusing on the cis- and trans-elements in promoters however, the role of mRNA export machinery during differentiation has not been adequately examined. THO (Suppressors of the transcriptional defects of hpr1 delta by overexpression) complex 5 (THOC5) is a member of THO complex which is a subcomplex of the transcription/export complex (TREX). THOC5 is evolutionarily conserved in higher eukaryotes, however the exact roles of THOC5 in transcription and mRNA export are still unclear. In this review, we focus on recently uncovered aspects of the role of THOC5 in signal transduction induced by extracellular stimuli. THOC5 is phosphorylated by several protein kinases at multiple residues upon extracellular stimuli. These include stimulation with growth factors/cytokines/chemokines, or DNA damage reagents. Furthermore, THOC5 is a substrate for several oncogenic tyrosine kinases, suggesting that THOC5 may be involved in cancer development. Recent THOC5 knockout mouse data reveal that THOC5 is an essential element in the maintenance of stem cells and growth factor/cytokine-mediated differentiation/proliferation. Furthermore, depletion of THOC5 influences less than 1% of total mRNA export in the steady state, however it influences more than 90% of growth factor/cytokine induced genes. THOC5, thereby contributes to the 3' processing and/or export of immediate-early genes induced by extracellular stimuli. These studies bring new insight into the link between the mRNA export complex and immediate-early gene response. The data from these studies also suggest that THOC5 may be a useful tool for studying stem cell biology, for modifying the differentiation processes and for cancer therapy.

Project description:THOC5, a member of the mRNA export complex, is essential for hematopoiesis in vivo and is required for CSF-1 induced macrophage differentiation, thereby playing a key role in the mRNA export of immediate early genes induced by CSF-1 stimulation. Hematopoiesis, growth, differentiation, and commitment to a restricted lineage are guided by a timely expressed set of cytokine receptors and their down-stream transcription factor genes. Transcriptional control mechanisms of gene expression during differentiation were mainly studied by focusing on the cis- and trans-element in promoters, however, the role of mRNA export machinery during differentiation have not been adequately examined. A member of the mRNA export complex, THOC5 which is a substrate for the macrophage-colony stimulating factor (CSF-1) receptor, ATM kinase, or protein kinase C, is an essential element in the maintenance of hematopoiesis in adult mice. Using tamoxifen inducible THOC5 knockout mice, we show here that the depletion of THOC5 impaired myeloid differentiation, but does not influence terminally differentiated organs. Furthermore, an in vitro study showed that the depletion of THOC5 in bone marrow cells results in abnormal CSF-1 induced macrophage differentiation. Transcriptome analysis using cytoplasmic RNA derived from macrophages reveals that only 99 genes were down-regulated 3 days after the depletion of THOC5, however, immediate early genes induced by CSF-1 stimulation, such as Ets family genes, and regulators of myeloid differentiation HoxA1, Id1, Id3 were THOC5 direct target mRNAs, suggesting that THOC5 plays a key role in myeloid differentiation. In each of two biological experiments (called rep1 and rep2 below) six different cytoplasmic RNA samples were generated from bone marrow derived macrophages. These different samples (conditions) correspond to: 1) Cells from ERT2 Cre control mice at day 0, 2) Cells from ERT2 Cre control mice at day 3 of differentiation, 3) Cells from ERT2 Cre control mice at day 3 of differentiation stimulated with tamoxifen, 4) Cells from ERT2 Cre Thoc5 (flox/flox) mice at day 0, 5) Cells from ERT2 Cre Thoc5 (flox/flox) mice at day 3 of differentiation, 6) Cells from ERT2 Cre Thoc5 (flox/flox) mice at day 3 of differentiation stimulated with tamoxifen. Day 0 samples of a given genotype were utilized as common reference in two microarrays and were accordingly co-hydridized against both 3-days differentiated samples (treated or none with tamoxifen) of the same genotype and biological experiment. Thus, four dual-color microarrays from each of the two biological replicate series were performed (giving rise to 8 dual-color microarrays in total). The complete set of microarrays from the second biological experiment (rep2) was performed with inverted labeling directions (dye-swap approach).

Dataset Information

THOC5, a member of the mRNA export complex, contributes to processing of a subset of wingless/integrated (Wnt) target mRNAs and integrity of the gut epithelial barrier.

Publications

THOC5, a member of the mRNA export complex, contributes to processing of a subset of wingless/integrated (Wnt) target mRNAs and integrity of the gut epithelial barrier.

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