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Characterization of the effects of CIC loss and neomorphic IDH1 mutation on the transcriptome and epigenome Lee, Stephen D.

Abstract

The Capicua transcriptional repressor (CIC) is a transcription factor whose target genes are relieved from its repressive activity upon activation of receptor tyrosine kinase signalling. Loss of CIC function is implicated in oligodendroglioma (ODG) etiology, since ODGs are defined by loss of heterozygosity of CIC (through chromosome 1p/19q loss) and exhibit deleterious somatic mutation in the remaining allele in 50-80% of cases. However, CIC’s role in this context remains obscure, primarily from our currently limited knowledge regarding its biological functions. Moreover, CIC mutations are invariably found in ODGs with a neomorphic IDH1 or IDH2 mutation, yet the functional relationship between these two genetic events are also unclear. Global epigenetic alterations are established to result from the downstream effects of mutant IDH1/2 and CIC was recently identified to physically interact with various chromatin modulators, highlighting the relevance of epigenetic regulation in CIC function as well. Under the hypothesis that CIC and mutant IDH1/2 cooperatively dysregulate gene expression to contribute to ODG, we performed transcriptomic and epigenomic profiling of CIC-wildtype (WT) and CIC-knockout (KO) cell lines, with and without mutant IDH1 expression. Comprehensive analyses across these molecular landscapes revealed a recurrence of neurodevelopmental gene dysregulation in association with CIC loss. CIC ChIP-seq was also performed to expand upon the currently limited ensemble of known CIC target genes. Among the newly identified direct CIC target genes were EPHA2 and ID1, whose functions are linked to neurodevelopment and the tumourigenicity of in vivo glioma tumour models. NFIA, a known mediator of gliogenesis, was discovered to be uniquely overexpressed in cells with both mutant IDH1 and lack of functional CIC. These results illuminate neurodevelopment and specific genes within this context as candidate targets through which CIC alterations may contribute to the onset or early progression of IDH-mutant gliomas.

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