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.
Highlights
MicroRNAs are a large class of small noncoding RNAs that act as posttranscriptional regulators of gene expression [1]. miRNAs simultaneously modulate the expression of several targets by binding to the 3’-untraslated region (3’-UTR) of the mRNAs, resulting in mRNA destabilization and/or translational inhibition [2]
MiR-382-5p overexpression has been described in some hematological malignancies, such as Primary Myelofibrosis (PMF) [12] and Acute Myeloid Leukemia (AML) [10, 11], even if its role in normal hematopoiesis was still unknown
We demonstrated that miR-382-5p supports the expansion of granulocyte lineage whereas negatively interferes with megakaryocyte commitment, as demonstrated by a significant increase of granulocyte precursors coupled to decrease of megakaryocyte ones in miR-382-5p-overexpressing cells (Figure 1-3)
Summary
MicroRNAs (miRNAs) are a large class of small noncoding RNAs that act as posttranscriptional regulators of gene expression [1]. miRNAs simultaneously modulate the expression of several targets by binding to the 3’-untraslated region (3’-UTR) of the mRNAs, resulting in mRNA destabilization and/or translational inhibition [2]. The combinatorial expression of miRNAs can precisely characterize specific cell types and regulate different phases of differentiation [3, 4]. Recent advancements in computational and molecular biology have highlighted the existence of regulatory networks where miRNAs modulate the expression of transcription factors and transcription factors regulate miRNA levels to promote or maintain some important cell functions [1]. MiRNA expression deregulation may contribute to the development of different human diseases, including cancer [5]. In order to characterize the function of miR-382-5p in myeloid development, we evaluated the effects of its overexpression on the commitment of human CD34+ hematopoietic stem/progenitor cells (HSPCs). We identified MAX dimerization protein 1 (MXD1) as a target of miR-382-5p, and demonstrated that miR-382-5p favours granulocyte lineage at the expense of megakaryocyte one through MXD1 downregulation
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