PRC2 activates interferon-stimulated genes indirectly by repressing miRNAs in glioblastoma

• Published in: PloS one 2019-09, Vol.14 (9), p.e0222435-e0222435
• Main Authors: Shivram, Haridha, Le, Steven V, Iyer, Vishwanath R
• Format: Article
• Language: English
• Subjects: Analysis; Astrocytoma; Binding; Binding sites; Biochemistry; Biological response modifiers; Biology and life sciences; Book publishing; Brain cancer; Cancer; Care and treatment; Chromatin; Chromosome 14; Chromosomes; Cytokines; DNA Methylation; Domains; Enhancer of Zeste Homolog 2 Protein - genetics; Enhancer of Zeste Homolog 2 Protein - metabolism; Epigenesis, Genetic; Epigenetics; Gene expression; Gene Expression Regulation - genetics; Genes; Genetic aspects; Genetic regulation; Genomes; Glioblastoma; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastomas; Gliomas; Health aspects; Histone H3; Histones - metabolism; Humans; Interferon; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - metabolism; Interferons - metabolism; Loci; Methyltransferase; MicroRNA; MicroRNAs; MicroRNAs - genetics; miRNA; Molecular biology; Mutagenesis; Polycomb group proteins; Polycomb Repressive Complex 2 - genetics; Polycomb Repressive Complex 2 - metabolism; Preadipocyte factor 1; Regulators; Ribonucleic acid; RNA; Stem cells; Transferases; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0222435

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.