Transcriptional condensates enrich phosphorylated PRMT2 to stimulate H3R8me2a deposition and hypoxic response in glioblastoma

Histone arginine methylation by protein arginine methyltransferases (PRMTs) is crucial for transcriptional regulation and is implicated in cancers. Despite their therapeutic potential, some PRMTs present challenges as drug targets due to their context-dependent activities. Here, we demonstrate that hypoxia triggers the rapid condensation of PRMT2, which is essential for its histone H3R8 asymmetric dimethylation (H3R8me2a) activity. This process depends on PRMT2’s integration into transcriptional condensates, which is mediated by phosphorylation at Serine 12 within its N-terminal intrinsically disordered region. This phosphorylation is critical for hypoxia-inducible gene expression and glioblastoma (GBM) progression. Transcription-associated cyclin-dependent kinases (CDKs), particularly CDK9, drive PRMT2S12 phosphorylation. Inhibition of CDK9 using TG02 suppresses hypoxia-induced H3R8me2a and transcriptional activity. Moreover, the combination of TG02 and temozolomide, the standard chemotherapy for GBM, significantly inhibits tumor progression in mouse xenograft models, an effect partially mediated by targeting PRMT2S12 phosphorylation. Our study uncovers the role of transcriptional condensation in enhancing PRMT activity, reveals a new mechanism for CDK9 inhibitors in modulating context-dependent transcriptional programs, and proposed a combinatorial therapeutic strategy against GBM.