title: Epigenetic silencing of the oncogenic miR-17-92 cluster during PU.1-directed macrophage differentiation.
abstract: The oncogenic cluster miR-17-92 encodes seven related microRNAs that regulate cell proliferation, apoptosis and development. Expression of miR-17-92 cluster is decreased upon cell differentiation. Here, we report a novel mechanism of the regulation of miR-17-92 cluster. Using transgenic PU.1(-/-) myeloid progenitors we show that upon macrophage differentiation, the transcription factor PU.1 induces the secondary determinant Egr2 which, in turn, directly represses miR-17-92 expression by recruiting histone demethylase Jarid1b leading to histone H3 lysine K4 demethylation within the CpG island at the miR-17-92 promoter. Conversely, Egr2 itself is targeted by miR-17-92, indicating existence of mutual regulatory relationship between miR-17-92 and Egr2. Furthermore, restoring EGR2 levels in primary acute myeloid leukaemia blasts expressing elevated levels of miR-17-92 and low levels of PU.1 and EGR2 leads to downregulation of miR-17-92 and restored expression of its targets p21CIP1 and BIM. We propose that upon macrophage differentiation PU.1 represses the miR-17-92 cluster promoter by an Egr-2/Jarid1b-mediated H3K4 demethylation mechanism whose deregulation may contribute to leukaemic states.
authors: Institute of Pathological Physiology and Center of Experimental Hematology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors: Vit
authors: V
authors: Pospisil
authors: Karin
authors: K
authors: Vargova
authors: Juraj
authors: J
authors: Kokavec
authors: Jana
authors: J
authors: Rybarova
authors: Filipp
authors: F
authors: Savvulidi
authors: Anna
authors: A
authors: Jonasova
authors: Emanuel
authors: E
authors: Necas
authors: Jiri
authors: J
authors: Zavadil
authors: Peter
authors: P
authors: Laslo
authors: Tomas
authors: T
authors: Stopka
mesh_terms: D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D051767:Early Growth Response Protein 2 / Q000378:metabolism / Q000502:physiology; D044127:Epigenesis, Genetic / Q000502:physiology*; D020868:Gene Silencing / Q000502:physiology; D018014:Gene Transfer Techniques; D018922:HL-60 Cells; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism / Q000502:physiology; D008264:Macrophages / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D005810:Multigene Family / Q000235:genetics; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D062085:RNA, Long Noncoding; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology; D012689:Sequence Homology, Nucleic Acid; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D051767:Early Growth Response Protein 2; D056484:Jumonji Domain-Containing Histone Demethylases; D035683:MicroRNAs; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D062085:RNA, Long Noncoding; D012097:Repressor Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C497326:EGR2 protein, human; C568997:MIR17HG, human; C524941:MIRN17 microRNA, human; C119611:KDM5B protein, human