Krista A. Budinich, Xinyi Yao, Chujie Gong, Lele Song, Xiaoting Wang, Michelle C. Lee, Kaeli M. Mathias, Qinglan Li, Sylvia Tang, Yiman Liu, Son C. Nguyen, Eric F. Joyce, Yuanyuan Li, Haitao Li, Liling Wan.
RNA reinforces condensate nucleation on chromatin to amplify oncogenic transcription, Molecular Cell, 2026, ISSN 1097-2765, DOI: https://doi.org/10.1016/j.molcel.2026.05.024 (https://www.sciencedirect.com/science/article/pii/S1097276526003485)

Summary

Aberrant chromatin-associated condensates have emerged as drivers of transcriptional dysregulation in cancer, yet how extrinsic factors modulate their assembly and function remains poorly understood. Gain-of-function mutations in the chromatin reader ENL (“Eleven-nineteen-leukemia”) drive oncogenesis by inducing condensate formation at select target loci. Here, we demonstrate that locally produced transcripts reinforce the nucleation, chromatin engagement, and oncogenic activity of mutant ENL condensates. Mutant ENL binds to RNA in part through a basic patch within its YEATS domain, and this interaction enhances condensate formation in vitro and in cells. Using a chemically inducible condensate displacement and renucleation system, we show that blocking ENL-RNA interactions or transcription impairs condensate reformation at endogenous targets. RNA binding preferentially enhances mutant ENL occupancy and transcriptional bursting at condensate-permissive loci. In mouse models, disrupting RNA binding suppresses mutant ENL-driven oncogenic transcription and leukemogenesis. These findings reveal how chromatin-associated oncogenic proteins hijack local transcripts to reinforce condensate nucleation and drive tumorigenesis.