Recent advancement in understanding cancer etiology has highlighted epigenetic deregulation as an important phenomenon leading to poor prognosis in glioblastoma (GBM). Polycomb repressive complex 2 (PRC2) is one such important epigenetic modifier reportedly altered in GBM. However, its defined mechanism in tumorigenesis still remains elusive. In present study, we analyzed our in‐house ChIPseq data for H3k27me3 modified miRNAs and identified miR‐490‐3p to be the most common target in GBM with significantly downregulated expression in glioma patients in both TCGA and GBM patient cohort. Our functional analysis delineates for the first time, a central role of PRC2 catalytic unit EZH2 in directly regulating expression of this miRNA and its host gene CHRM2 in GBM. In accordance, cell line treatment with EZH2 siRNA and 5‐azacytidine also confirmed its coregulation by CpG and histone methylation based epigenetic mechanisms. Furthermore, induced overexpression of miR‐490‐3p in GBM cell lines significantly inhibited key hallmarks including cellular proliferation, colony formation and spheroid formation, as well as epithelial‐to‐mesenchymal transition (EMT), with downregulation of multiple EMT transcription factors and promigratory genes (MMP9, CCL5, PIK3R1, ICAM1, ADAM17 and NOTCH1). We also for the first time report TGFBR1 and TGIF2 as two direct downstream effector targets of miR‐490‐3p that are also deregulated in GBM. TGIF2, a novel target, was shown to promote migration and EMT that could partially be rescued by miR‐490‐3p overexpression. Overall, this stands as a first study that provides a direct link between epigenetic modulator EZH2 and oncogenic TGF‐β signaling involving novel miR‐490‐3p/TGIF2/TGFBR1 axis, that being targetable might be promising in developing new therapeutic intervention strategies for GBM.

MicroRNAs (miRNAs) are small non‐coding RNAs that function as posttranscriptional gene regulators. Among a pool of >2600 known human mature miRNAs, only a small subset have been functionally interrogated and a further smaller pool shown to be associated with the pathogenesis of a variety of diseases suggesting their critical role in maintaining homeostasis. Here, we draw your attention to one such miRNA, miR‐490, that has been reported to be deregulated in a myriad of diseases (23 diseases) ranging from cardiomyopathy, depression, and developmental disorders to many cancer types (28 cancer types), such as hepatocellular carcinoma, gastric cancer, cancers of the reproductive and central nervous system among others. The prognostic and diagnostic potential of miR‐490 has been reported in many diseases including cancer underlining its clinical relevance. We also collate a complex plethora of epigenetic (histone and DNA methylation), transcriptional (TF), and posttranscriptional (lncRNA and circRNA) mechanisms that have been shown to tightly regulate miR‐490 levels. The targets of miR‐490 involve a range of cancer‐related genes involved in the regulation of various cancer hallmarks like cell proliferation, migration, and invasion, apoptotic cell death, angiogenesis, and so forth. Overall, our in‐depth review highlights for the first time the emerging role of miR‐490 in disease pathology, diagnosis, and prognosis that assigns a unique therapeutic potential to miR‐490 in the era of precision medicine.

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Glioblastoma multiforme (GBM) encompasses brain malignancies marked by phenotypic and transcriptional heterogeneity thought to render these tumors aggressive, resistant to therapy, and inevitably recurrent. However, little is known about how the spatial organization of GBM genomes underlies this heterogeneity and its effects. Here, we compiled a cohort of 28 patient-derived glioblastoma stem cell-like lines (GSCs) known to reflect the properties of their tumor-of-origin; six of these were primary-relapse tumor pairs from the same patient. We generated and analyzed kbp-resolution chromosome conformation capture (Hi-C) data from all GSCs to systematically map >3,100 standalone and complex structural variants (SVs) and the >6,300 neoloops arising as a result. By combining Hi-C, histone modification, and gene expression data with chromatin folding simulations, we explain how the pervasive, uneven, and idiosyncratic occurrence of neoloops sustains tumor-specific transcriptional programs via the formation of new enhancer-promoter contacts. We also show how even moderately recurrent neoloops can help us infer patient-specific vulnerabilities. Together, our data provide a resource for dissecting GBM biology and heterogeneity, as well as for informing therapeutic approaches.

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