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

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.

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

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.

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.

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.