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.
Highlights
Polycomb repressive complex 2 (PRC2) is an epigenetic modifier complex that binds near transcription start sites and elsewhere in the genome and silences genes by methylating histone H3 at K27 through its histone methyltransferase component EZH2. [1]
We identified genes stimulated in response to type I interferon (IFN-α) and type II interferon (IFN-γ) and checked for the number of interferon-stimulated genes (ISGs) that were regulated by EZH2
We found that 40% of the genes regulated by EZH2 were ISGs (P = 9.6e-89)
Summary
PRC2 (polycomb repressive complex 2) is an epigenetic modifier complex that binds near transcription start sites and elsewhere in the genome and silences genes by methylating histone H3 at K27 through its histone methyltransferase component EZH2. [1]. PRC2 (polycomb repressive complex 2) is an epigenetic modifier complex that binds near transcription start sites and elsewhere in the genome and silences genes by methylating histone H3 at K27 through its histone methyltransferase component EZH2. Several cancers including GBM, are characterized by upregulation of multiple components of the PRC2 complex including EZH2 [2,3,4]. PRC2 could play an oncogenic role by silencing tumor-suppressive protein-coding genes or non-coding RNAs. miRNAs are a class of ~22 nucleotide (nt) short non-coding RNAs that play significant regulatory roles in disease and developmental pathways. Several miRNAs have been identified that play both oncogenic and tumor suppressive functions in multiple cancers including GBM [5, 6].
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