Transcriptional condensates enrich phosphorylated PRMT2 to stimulate H3R8me2a deposition and hypoxic response in cancers-RNA-seq

Histone arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is crucial for transcription regulation and increasingly associated with cancer progression. However, some PRMTs present challenges as drug targets due to their unique, context-dependent activities. Here we report that hypoxia induces rapid condensation of PRMT2, which is required for its activity on histone H3R8 asymmetric dimethylation (H3R8me2a). Consistent with its roles in transcription activation, PRMT2 is enriched in transcriptional condensates and relies on its phosphorylation at Ser 12 (PRMT2S12ph). This phosphorylation, situated within the N-terminal intrinsic disordered regions of PRMT2, facilitates its integration into transcriptional condensates and H3R8me2a deposition. Consequently, PRMT2S12 phosphorylation is indispensable for transcription activation of the hypoxia-inducible genes and tumor progression in vivo. Notably, transcription-associated Cyclin-Dependent Kinases (CDK7-CDK9) is imperative for PRMT2S12 phosphorylation. As a result, CDK9 inhibitors suppress hypoxia-induced H3R8me2a activity and transcription, and they synergize with Temozolomide (TMZ) in halting tumor progression, partly reliant on blocking PRMT2S12ph. Therefore, our study uncovers novel roles of transcriptional condensation in augmenting methyltransferase activity and provide a fresh anti-cancer mechanism for CDK9 inhibitors by restricting context-dependent transcriptional programs.