title: miR-382-5p Controls Hematopoietic Stem Cell Differentiation Through the Downregulation of MXD1.
abstract: microRNAs are key regulators of gene expression that control stem cell fate by posttranscriptional downregulation of hundreds of target genes through seed pairing in their 3' untranslated region. In fact, miRNAs tightly regulate fundamental stem cell processes, like self-renewal, proliferation, and differentiation; therefore, miRNA deregulation may contribute to the development of solid tumors and hematological malignancies. miR-382-5p has been found to be upregulated in patients with myeloid neoplasms, but its role in normal hematopoiesis is still unknown. In this study, we demonstrated that miR-382-5p overexpression in CD34(+) hematopoietic stem/progenitor cells (HSPCs) leads to a significant decrease of megakaryocyte precursors coupled to increase of granulocyte ones. Furthermore, by means of a computational analysis using different prediction algorithms, we identified several putative mRNA targets of miR-382-5p that are downregulated upon miRNA overexpression (ie, FLI1, GATA2, MAF, MXD1, RUNX1, and SGK1). Among these, we validated MXD1 as real target of miR-382-5p by luciferase reporter assay. Finally, we showed that MXD1 knockdown mimics the effects of miR-382-5p overexpression on granulocyte and megakaryocyte differentiation of CD34(+) cells. Overall, our results demonstrated that miR-382-5p expression favors the expansion of granulocyte lineage and impairs megakaryocyte commitment through MXD1 downregulation. Therefore, our data showed for the first time that the miR-382-5p/MXD1 axis plays a critical role in myelopoiesis by affecting the lineage choice of CD34(+) HSPCs.
authors: 1 Centre for Regenerative Medicine "Stefano Ferrari," Department of Life Sciences, University of Modena and Reggio Emilia , Modena, Italy .
authors: Roberta
authors: R
authors: Zini
authors: 1 Centre for Regenerative Medicine "Stefano Ferrari," Department of Life Sciences, University of Modena and Reggio Emilia , Modena, Italy .
authors: Chiara
authors: C
authors: Rossi
authors: 1 Centre for Regenerative Medicine "Stefano Ferrari," Department of Life Sciences, University of Modena and Reggio Emilia , Modena, Italy .|2 Haematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford , Oxford, United Kingdom .
authors: Ruggiero
authors: R
authors: Norfo
authors: 1 Centre for Regenerative Medicine "Stefano Ferrari," Department of Life Sciences, University of Modena and Reggio Emilia , Modena, Italy .
authors: Valentina
authors: V
authors: Pennucci
authors: 1 Centre for Regenerative Medicine "Stefano Ferrari," Department of Life Sciences, University of Modena and Reggio Emilia , Modena, Italy .
authors: Greta
authors: G
authors: Barbieri
authors: 1 Centre for Regenerative Medicine "Stefano Ferrari," Department of Life Sciences, University of Modena and Reggio Emilia , Modena, Italy .
authors: Samantha
authors: S
authors: Ruberti
authors: 1 Centre for Regenerative Medicine "Stefano Ferrari," Department of Life Sciences, University of Modena and Reggio Emilia , Modena, Italy .
authors: Sebastiano
authors: S
authors: Rontauroli
authors: 1 Centre for Regenerative Medicine "Stefano Ferrari," Department of Life Sciences, University of Modena and Reggio Emilia , Modena, Italy .
authors: Simona
authors: S
authors: Salati
authors: 1 Centre for Regenerative Medicine "Stefano Ferrari," Department of Life Sciences, University of Modena and Reggio Emilia , Modena, Italy .
authors: Elisa
authors: E
authors: Bianchi
authors: 1 Centre for Regenerative Medicine "Stefano Ferrari," Department of Life Sciences, University of Modena and Reggio Emilia , Modena, Italy .
authors: Rossella
authors: R
authors: Manfredini
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002999:Clone Cells; D003094:Collagen / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D020868:Gene Silencing / Q000187:drug effects; D017930:Genes, Reporter; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008747:Methylcellulose / Q000494:pharmacology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: D018952:Antigens, CD34; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C555413:MIRN382 microRNA, human; C079439:MXD1 protein, human; D035683:MicroRNAs; D012097:Repressor Proteins; D008747:Methylcellulose; D003094:Collagen; D008156:Luciferases