RNA promotes nucleation and oncogenic activity of chromatin-associated condensates [RNA-Seq]

Aberrant chromatin-associated condensates have emerged as drivers of gene dysregulation in cancer, yet the mechanisms regulating their formation and function remain poorly understood. Mutations in the histone acetylation reader ENL, recurrent in leukemia and Wilms tumor, drive oncogenesis by inducing condensate formation at selective target loci. Here, we show that RNA promotes the nucleation, chromatin engagement, and oncogenic activity of ENL mutant condensates. Mutant ENL binds RNA via a conserved basic patch within the YEATS domain, and this interaction enhances condensate formation in vitro and in cells. Acute displacement and reassembly experiments demonstrate that interactions with local RNA transcripts facilitate condensate nucleation efficiency at endogenous target loci. Partial disruption of RNA binding preferentially impairs chromatin occupancy of ENL mutants at condensate-permissive loci, leading to reduced transcriptional bursting and target gene expression. In mouse models, disrupting RNA binding compromises mutant ENL-driven gene expression and malignant self-renewal, halting disease progression and prolonging survival. These findings uncover a previously unrecognized role of RNA in promoting the formation and oncogenic function of chromatin-associated condensate.