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

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.

Loss of histone H3 trimethylation on lysine 27 and nuclear expression of transducin‐like enhancer 1 in primary intracranial sarcoma, DICER1‐mutant

“…The DICER1 gene product is an RNase III endoribonuclease that functions canonically in the microRNA (miRNA) biogenesis pathway, where it cleaves miRNAs from their hairpin‐shaped precursors 21 . Although it is possible that loss of H3K27me3 in primary CNS sarcoma, DICER1 ‐mutated occurs as a result of interactions between miRNAs and PRC2, 22,23 the mechanism beyond the loss of trimethylation in these tumours is not elucidated. It is important to note the concept of a mosaic expression pattern of H3K27me3 immunostaining.…”

Polycomb proteins control floral determinacy by H3K27me3-mediated repression of pluripotency genes in Arabidopsis thaliana

“…In multicellular eukaryotes, including plants, H3K27me3 plays a fundamental role in the epigenetic regulation of tissue-specific expression patterns, which silences its direct targets and promotes gene expression indirectly by repressing miRNA genes (Lafos et al, 2011;Shivram et al, 2019). Although it has been implicated that PcG proteins can indirectly activate their own expression during seed development (Baroux et al, 2006), we provide here genetic evidence that PcG proteins indirectly activate TF genes by silencing of upstream transcriptional repressors.…”

The function of histone methylation and acetylation regulators in GBM pathophysiology

“…EZH2 also contributes to the immunosuppressive microenvironment of GBM by triggering specific cytokine expression, maintaining expression of interferon-stimulated genes that promote a M2 microglial phenotype in an iNOS and TGF-β2-dependent manner. Evasion of NK cell immune surveillance occurs via a circular EZH2 encoded protein (EZH2-92aa) that directly binds the promoters of genes (MICA/B, ULBP) necessary for the expression of NK group 2D ligands in GSCs, leading to decreased transcription and ultimately decreased NK cell-mediated tumor cell death ( 14 , 139 , 142 , 143 ). The role of EZH2 in promoting GBM invasiveness via regulation of AXL in a histone modification-independent manner has been demonstrated in vitro with EZH2 knockdown ( 127 ).…”