Integrated transcriptomic analysis reveals KRAS-associated gene activation and epigenetic regulation in mutant IDH1 glioma.

Abstract

Background: Mutations in isocitrate dehydrogenase 1 (IDH1) are hallmark features of diffuse gliomas and drive extensive metabolic and epigenetic reprogramming through accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). However, the downstream transcriptional programs and chromatin-based mechanisms linking mutant IDH1 to oncogenic signaling remain incompletely understood.

Objective: This study aimed to define transcriptional changes associated with the IDH1 R132H mutation and to determine how epigenetic mechanisms influence KRAS-associated gene expression.

Methods: We analyzed transcriptomic data from the TCGA-LGG cohort and public RNA-seq datasets to identify differentially expressed genes and enriched pathways. Key findings were validated using qRT-PCR in cellular models expressing IDH1 R132H. To assess epigenetic regulation, we performed knockdown experiments targeting the H3K36 methyltransferases SETD2 and SMYD5.

Results: Integrated transcriptomic analyses revealed consistent enrichment of KRAS signaling-related gene signatures in IDH1 R132H tumors and cell models. qRT-PCR validation confirmed altered expression of key KRAS-associated genes involved in immune response, extracellular matrix remodeling, and tumor-related processes. Notably, the knockdown of SETD2 or SMYD5 significantly reduced the expression of these genes, indicating that H3K36 methylation-associated chromatin regulation contributes to their transcriptional activation.

Conclusion: These findings demonstrate that mutant IDH1 promotes KRAS-associated transcriptional programs, at least in part, through epigenetic mechanisms involving H3K36 methylation-dependent chromatin regulation in glioma.