Gfi1 regulates miR-21 and miR-196b to control myelopoiesis
| Autor: | H. Leighton Grimes, Avinash M. Baktula, Chinavenmeni S. Velu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Male
Chromatin Immunoprecipitation Myeloid medicine.medical_treatment Immunology Immunoblotting Electrophoretic Mobility Shift Assay Granulocyte Biology Biochemistry Granulopoiesis Colony-Forming Units Assay Phagocytes Granulocytes and Myelopoiesis Mice Bone Marrow microRNA Granulocyte Colony-Stimulating Factor medicine Animals RNA Small Interfering Bone Marrow Transplantation Oligonucleotide Array Sequence Analysis Zinc finger Mice Knockout Myelopoiesis Mice Inbred BALB C Growth factor Gene Expression Profiling Cell Biology Hematology Flow Cytometry Hematopoietic Stem Cells Molecular biology DNA-Binding Proteins Mice Inbred C57BL Haematopoiesis MicroRNAs medicine.anatomical_structure Cancer research Female Granulocytes Transcription Factors |
| Popis: | The zinc finger protein growth factor independent-1 (Gfi1) is a transcriptional repressor that is critically required for normal granulocytic differentiation. GFI1 loss-of-function mutations are found in some patients with severe congenital neutropenia (SCN). The SCN-associated GFI1-mutant proteins act as dominant negatives to block granulopoiesis through selective deregulation of a subset of GFI1 target genes. Here we show that Gfi1 is a master regulator of microRNAs, and that deregulated expression of these microRNAs recapitulates a Gfi1 loss-of-function block to granulocyte colony-stimulating factor (G-CSF)–stimulated granulopoiesis. Specifically, bone marrow cells from a GFI1-mutant SCN patient and Gfi1−/− mice display deregulated expression of miR-21 and miR-196B expression. Flow cytometric analysis and colony assays reveal that the overexpression or depletion of either miR induces changes in myeloid development. However, coexpression of miR-21 and miR-196b (as seen in Gfi1−/− mice and a GFI1N382S SCN patient) completely blocks G-CSF–induced granulopoiesis. Thus, our results not only identify microRNAs whose regulation is required during myelopoiesis, but also provide an example of synergy in microRNA biologic activity and illustrate potential mechanisms underlying SCN disease pathogenesis. |
| Databáze: | OpenAIRE |
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