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Cited by 93MicroRNA in disease regulationEpigenetics and DNA MethylationAcute Myeloid Leukemia Research

Epigenetic silencing of the oncogenic miR‐17‐92 cluster during PU.1‐directed macrophage differentiation

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Pospisil, Vit, Vargova, Karin, Kokavec, Juraj, Rybarova, Jana, Savvulidi, Filipp, Jonasova, Anna, Necas, Emanuel, Zavadil, Jiri +2 more·2011·The EMBO Journal
DOI 10.1038/emboj.2011.317PMC PMC3230374
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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.

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  • Egr2 can collaborate with PU.1 in positive regulation when co-bound with it, but has also been implicated as a PU.1-stimulated repressor of the mir17~92 complex.

    “Egr2, for example, can collaborate with PU.1 in positive regulation when co-bound with it (106), but has also been implicated as a PU.1-stimulated repressor of the mir17~92 complex (107).”

    From Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development (2019) · cites this paper as [107]

  • PU.1 represses the miR-17-92 cluster promoter through histone demethylation.

    “PU.1 represses the miR-17-92 cluster promoter, which encodes for miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-92a, through histone demethylation [186].”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [186]

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Cited by

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Authors
Pospisil, V., Vargova, K., Kokavec, J., Rybarova, J., Savvulidi, F., Jonasova, A., Necas, E., Zavadil, J., Laslo, P., & Stopka, T.
Affiliations
  • Charles University (CZ)
  • General University Hospital in Prague (CZ)
  • St James's University Hospital (GB)
ORCID
Venue
The EMBO Journal
Publisher
Springer Science and Business Media LLC
Published
2011-09-06
Volume
30
Issue
21
Pages
4450-4464
ISSN
  • 0261-4189 (ISSN-L)
  • 1460-2075
DOI
10.1038/emboj.2011.317
PMC
PMC3230374
OpenAlex
W1804959557
Cited by
93
References
6
Citations by year
2026: 1 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 5 · 2021: 2 · 2020: 3 · 2019: 4 · 2018: 7 · 2017: 8 · 2016: 7 · 2015: 8 · 2014: 8 · 2013: 25 · 2012: 9
FWCI
4.68
Type
journal article
Language
en
Open access
Licence
Locations
  • The EMBO Journal (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • NYU Langone Medical Center
  • King's College London
  • National Institutes of Health (CA016087)
  • University of Illinois at Urbana-Champaign
  • National Cancer Institute (CA 016087, MSM 0021620806, P30CA016087)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
Keywords
miR-17-92 cluster, PU.1, macrophage differentiation, EGR2, JARID1B, H3K4 demethylation, epigenetic silencing, microRNA regulation, acute myeloid leukemia, p21, building information modeling, myeloid progenitor cells, CpG islands
MeSH terms
Proto-Oncogene Protein Spi-1, Animals, Base Sequence, Cell Differentiation, Cells, Cultured, Multigene Family, Humans, Macrophages, Models, Biological, Nuclear Proteins, Proto-Oncogene Proteins, Repressor Proteins, Sequence Homology, Nucleic Acid, Transfection, Trans-Activators, Gene Transfer Techniques, HL-60 Cells, Gene Silencing, MicroRNAs, NIH 3T3 Cells, Epigenesis, Genetic, Mice, Early Growth Response Protein 2, Jumonji Domain-Containing Histone Demethylases, RNA, Long Noncoding

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