The microRNA-26a target E2F7 sustains cell proliferation and inhibits monocytic differentiation of acute myeloid leukemia cells

Salvatori, Beatrice; Iosue, Ilaria; Mangiavacchi, Arianna; Loddo, G; Padula, Fabrizio; Chiaretti, Sabina; Peragine, Nadia; Bozzoni, Irene; Fazi, Francesco; Fatica, Alessandro

doi:10.1038/cddis.2012.151

Cited by 67 publications

(57 citation statements)

References 40 publications

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“…miRNA 142-3p (miR-142-3p) and miR-29a, targeting TAB2 and CDK6, respectively, and both targeting CCNT2, are important regulators in monocytic differentiation (15). Downregulation of miR-17-5p, miR20a, miR-106a, and miR-26a is required for monocytopoiesis (16,17). During the induction of THP-1 cells by phorbol myristate acetate (PMA), increased expression of miR-155, miR-222, miR-424, and miR-503 was observed, and the combinatorial regulation of the four miRNAs was demonstrated to influence monocytic differentiation (18).…”

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confidence: 99%

PU.1-Regulated Long Noncoding RNA lnc-MC Controls Human Monocyte/Macrophage Differentiation through Interaction with MicroRNA 199a-5p

Chen

Lin

Shen

et al. 2015

Molecular and Cellular Biology

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Long noncoding RNAs (lncRNAs) are emerging as important regulators in mammalian development, but little is known about their roles in monocyte/macrophage differentiation. Here we identified a long noncoding monocytic RNA (lnc-MC) that exhibits increased expression during monocyte/macrophage differentiation of THP-1 and HL-60 cells as well as CD34؉ hematopoietic stem/progenitor cells (HSPCs) and is transcriptionally activated by PU.1. Gain-and loss-of-function assays demonstrate that lnc-MC promotes monocyte/macrophage differentiation of THP-1 cells and CD34 ؉ HSPCs. Mechanistic investigation reveals that lnc-MC acts as a competing endogenous RNA to sequester microRNA 199a-5p (miR-199a-5p) and alleviate repression on the expression of activin A receptor type 1B (ACVR1B), an important regulator of monocyte/macrophage differentiation. We also noted a repressive effect of miR-199a-5p on lnc-MC expression and function, but PU.1-dominant downregulation of miR-199a-5p weakens the role of miR-199a-5p in the reciprocal regulation between miR-199a-5p and lnc-MC. Altogether, our work demonstrates that two PU.1-regulated noncoding RNAs, lnc-MC and miR-199a-5p, have opposing roles in monocyte/macrophage differentiation and that lnc-MC facilitates the differentiation process, enhancing the effect of PU.1, by soaking up miR-199a-5p and releasing ACVR1B expression. Thus, we reveal a novel regulatory mechanism, comprising PU.1, lnc-MC, miR-199a-5p, and ACVR1B, in monocyte/macrophage differentiation.H ematopoiesis is a highly orchestrated process wherein the pluripotent self-renewing hematopoietic stem cells (HSCs) give rise to all blood cell lineages, including monocytes/macrophages (1). Monocytes/macrophages are mononuclear phagocytes that play crucial roles in innate immunity and the inflammatory response, and defects in their biogenesis and function can contribute to a broad spectrum of pathologies (2, 3). Control of monocyte/macrophage differentiation is a complex process requiring the coordinated expression of stage-specific transcription factors, cytokines, and noncoding RNAs (4, 5).PU.1 is a hematopoiesis-specific transcription factor that binds to a purine-rich sequence (GAGGAA) and regulates lineage-specific gene expression (6). Homozygous PU.1-deficient mice died at a late gestational stage, and PU.1 mutant embryos exhibited a defect in the generation of progenitors for monocytes and granulocytes (7). High expression of PU.1 in granulocyte-macrophage progenitors (GMPs) antagonizes C/EBP␣ function and favors monocyte development. Conversely, GMPs with low expression of PU.1 commit to granulocyte differentiation (8). In addition, transcription factors RUNX1, KLF4, and MafB are important regulators in monocyte/macrophage development (9-11). Colonystimulating factors (CSF), including granulocyte-macrophage CSF, granulocyte CSF, and CSF-1, also play fundamental roles in the early and late stages of the monocyte/macrophage differentiation process (12).MicroRNAs (miRNAs) are short (20-to 24-nucleotide [nt]) noncoding RNAs tha...

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confidence: 99%

PU.1-Regulated Long Noncoding RNA lnc-MC Controls Human Monocyte/Macrophage Differentiation through Interaction with MicroRNA 199a-5p

Chen

Lin

Shen

et al. 2015

Molecular and Cellular Biology

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“…C3-MSCs, transduced with miR 204 and miR 211, strongly downmodulate RUNX2 protein, but not CRTAP, a cartilage specific potential targetfor miR-204/211 (www.targets can.org). As a single gene product can be targeted by multiple miRNA species, and a single microRNA can target multiple mRNAs [7,28,32,1,22,34,13,3,15,38,9], additional targets of miR-204&211 might account for the disruption of chondrogenesis and hematopoietic supporting activity. Experiments with stable RUNX2 shRNA were performed to rule out the role for other targets of miR-204&211 impaired chondrogenesis and hematopoietic supporting activity.…”

Section: Discussionmentioning

confidence: 99%

“…Infective particles were produced and utilized as previously described [7,20]. Infection of C3 MSCs was performed as previously described [28].…”

Section: Lenti-mir204/211 Plasmids Generationmentioning

confidence: 99%

“…MicroRNAs (miRNAs) are 20-22 nt long single stranded RNAs that regulate gene expression by targeting complementary nucleic acid sequences [7,28,32,1,22,34,13,3]. Micro-RNAs play a regulatory role in virtually all cellular functions, including stemness [32], plasticity [1] and differentiation in many stem cell types including MSCs [32,1,22,34,13,3,11].…”

Section: Introductionmentioning

confidence: 99%

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Effect of miR-204&211 and RUNX2 control on the fate of human mesenchymal stromal cells

et al. 2017

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--MiR-204 and 211 enforced expression in murine mesenchymal stromal cells (MSCs) has been shown to induce adipogenesis and impair osteogenesis, through RUNX2 down-modulation. This mechanism has been suggested to play a role in osteoporosis associated with obesity. However, two further fundamental MSC functions, chondrogenesis and hematopoietic supporting activity, have not yet been explored. To this end, we transduced, by a lenti-viral vector, miR-204 and 211 in a model primary human MSC line, opportunely chosen among our MSC collection for displaying all properties of canonical bone marrow MSCs, except adipogenesis. Enforced expression of miR-204&211 in these cells, rescued adipogenesis, and inhibited osteogenesis, as previously reported in murine MSCs, but, surprisingly, also damaged cartilage formation and hematopoietic supporting activity, which were never explored before. RUNX2 has been previously indicated as the target of miR-204&211, whose down modulation is responsible for the switch from osteogenesis to adipogenesis. However, the additional disruption of chondrogenesis and hematopoietic supporting activity, which we report here, might depend on diverse miR-204&211 targets. To investigate this hypothesis, permanent RUNX2 knock-down was performed. Sh-RUNX2 fully reproduced the phenotypes induced by miR-204&211, confirming that RUNX2 down modulation is the major event leading to the reported functional modification on our MSCs. It seems thus apparent that RUNX2, a recognized master gene for osteogenesis, might rule all four MSC commitment and differentiation processes. Hence, the formerly reported role of miR204&211 and RUNX2 in osteoporosis and obesity, coupled with our novel observation showing inhibition of cartilage differentiation and hematopoietic support, strikingly resemble the clinical traits of metabolic syndrome, where osteoarthritis, osteoporosis, anaemia and obesity occur together. Our observations, corroborating and extending previous observations, suggest that miR-204&211-RUNX2 axis in human MSCs is possibly involved in the pathogenesis of this rapidly growing disease in industrialized countries, for possible therapeutic intervention to regenerate former homeostasis.

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“…Besides the abovementioned experimentally demonstrated targets for miR-34abc, translational repression of mRNAs encoding other cell cycle regulatory proteins in neutrophils, such as CDK4, CDK6, Notch, Cyclin E2, and Cyclin D1, may occur based on the reported effects of miR-34abc in other cell types [52]. E2F7 production is repressed by miR-26a during monocytic differentiation where E2F7 was found to inhibit transcription of p21Cip1 and be required for CDK2, CDK4, and CDK6 synthesis [53]. Expression of miR-26a increases twofold and miR-26b almost fivefold in a stepwise fashion from MB/PMs to BC/SCs [13].…”

Section: Regulation Of Cell Cyclementioning

confidence: 99%

MicroRNA Regulation of Neutrophil Function

Cowland

2014

MicroRNAs and Other Non-Coding RNAs in Inflammation

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Neutrophil maturation in the bone marrow, granulopoiesis, is a tightly regulated process governed by a temporal and successive expression of transcription factors and appropriate stimulation by cytokines from the surrounding stromal tissue of the bone marrow. Observations published over the last decade have, however, made it increasingly clear that posttranscriptional fine-tuning of protein expression by microRNAs (miRNAs) also plays a very important role in this process. In this chapter the influence of miRNAs on normal neutrophil development and biology is reviewed. The majority of miRNAs alter their expression profile at the point in granulopoiesis where proliferation ceases and terminal differentiation commences indicating a major role of miRNAs in fine-tuning of cell cycle regulatory proteins and transcription factors governing this transition. Some miRNAs are induced by external stimuli of the mature neutrophil and act to fine-tune the innate immune action of the cell.

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The microRNA-26a target E2F7 sustains cell proliferation and inhibits monocytic differentiation of acute myeloid leukemia cells

Cited by 67 publications

References 40 publications

PU.1-Regulated Long Noncoding RNA lnc-MC Controls Human Monocyte/Macrophage Differentiation through Interaction with MicroRNA 199a-5p

PU.1-Regulated Long Noncoding RNA lnc-MC Controls Human Monocyte/Macrophage Differentiation through Interaction with MicroRNA 199a-5p

Effect of miR-204&211 and RUNX2 control on the fate of human mesenchymal stromal cells

MicroRNA Regulation of Neutrophil Function

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