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Characterization of Functionally Associated miRNAs in Glioblastoma and their Engineering into Artificial Clusters for Gene Therapy
Published on: October 4, 2019
PRC2 activates interferon-stimulated genes indirectly by repressing miRNAs in glioblastoma
Haridha Shivram1, Steven V Le1, Vishwanath R Iyer1
1Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, Livestrong Cancer Institutes, University of Texas at Austin, Austin, Texas, United States of America.
Abstract:
Polycomb repressive complex 2 (PRC2) is a chromatin binding complex that represses gene expression by methylating histone H3 at K27 to establish repressed chromatin domains. PRC2 can either regulate genes directly through the methyltransferase activity of its component EZH2 or indirectly by regulating other gene regulators. Gene expression analysis of glioblastoma (GBM) cells lacking EZH2 showed that PRC2 regulates hundreds of interferon-stimulated genes (ISGs). We found that PRC2 directly represses several ISGs and also indirectly activates a distinct set of ISGs. Assessment of EZH2 binding proximal to miRNAs showed that PRC2 directly represses miRNAs encoded in the chromosome 14 imprinted DLK1-DIO3 locus. We found that repression of this locus by PRC2 occurs in immortalized GBM-derived cell lines as well as in primary bulk tumors from GBM and anaplastic astrocytoma patients. Through repression of these miRNAs and several other miRNAs, PRC2 activates a set of ISGs that are targeted by these miRNAs. This PRC2-miRNA-ISG network is likely to be important in regulating gene expression programs in GBM.
Insights
Polycomb repressive complex 2 (PRC2) regulates glioblastoma (GBM) gene expression by controlling interferon-stimulated genes (ISGs) and microRNAs (miRNAs). This complex establishes repressed chromatin domains, impacting GBM cell lines and patient tumors.
Area of Science:
- Epigenetics
- Molecular Biology
- Cancer Genomics
Background:
- Polycomb repressive complex 2 (PRC2) is a key epigenetic regulator.
- PRC2 establishes repressed chromatin domains via histone H3 lysine 27 trimethylation.
- PRC2 influences gene expression directly via EZH2 methyltransferase activity or indirectly via other regulators.
Purpose of the Study:
- To investigate the role of PRC2 in regulating interferon-stimulated genes (ISGs) in glioblastoma (GBM).
- To elucidate the mechanisms by which PRC2 controls gene expression networks in GBM.
- To identify novel therapeutic targets within the PRC2-miRNA-ISG axis in GBM.
Main Methods:
- Gene expression analysis in EZH2-deficient GBM cells.
- Assessment of EZH2 binding near microRNAs (miRNAs).
- Analysis of PRC2-mediated repression in GBM cell lines and patient tumors.
Main Results:
- PRC2 regulates hundreds of ISGs in GBM cells, both directly and indirectly.
- PRC2 directly represses miRNAs at the chromosome 14 imprinted DLK1-DIO3 locus.
- PRC2-mediated miRNA repression leads to the activation of specific ISGs in GBM.
Conclusions:
- PRC2 plays a significant role in regulating ISGs and miRNAs in GBM.
- A novel PRC2-miRNA-ISG regulatory network is identified in GBM.
- This network is crucial for controlling gene expression programs in GBM and represents a potential therapeutic target.
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