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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Base Sequence
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Cell Differentiation / genetics*
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Cells, Cultured
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Early Growth Response Protein 2 / metabolism
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Early Growth Response Protein 2 / physiology
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Epigenesis, Genetic / physiology*
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Gene Silencing / physiology
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Gene Transfer Techniques
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HL-60 Cells
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Humans
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Jumonji Domain-Containing Histone Demethylases / metabolism
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Jumonji Domain-Containing Histone Demethylases / physiology
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Macrophages / metabolism
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Macrophages / physiology*
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Mice
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MicroRNAs / genetics*
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MicroRNAs / metabolism
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Models, Biological
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Multigene Family / genetics
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NIH 3T3 Cells
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Nuclear Proteins / metabolism
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Nuclear Proteins / physiology
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins / physiology*
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RNA, Long Noncoding
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Repressor Proteins / metabolism
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Repressor Proteins / physiology
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Sequence Homology, Nucleic Acid
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Trans-Activators / physiology*
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Transfection
Substances
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EGR2 protein, human
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Early Growth Response Protein 2
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MIR17HG, human
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MIRN17 microRNA, human
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MicroRNAs
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Nuclear Proteins
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Proto-Oncogene Proteins
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RNA, Long Noncoding
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Repressor Proteins
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Trans-Activators
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proto-oncogene protein Spi-1
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Jumonji Domain-Containing Histone Demethylases
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KDM5B protein, human