Hotspot mutations in the structured ENL YEATS domain link aberrant transcriptional condensates and cancer

Growing evidence suggests prevalence of transcriptional condensates on chromatin, yet their mechanisms of formation and functional significance remain largely unclear. In human cancer, a series of mutations in the histone acetylation reader ENL create gain-of-function mutants with increased transcriptional activation abil-ity. Here, we show that these mutations, clustered in ENL's structured acetyl-reading YEATS domain, trigger aberrant condensates at native genomic targets through multivalent homotypic and heterotypic interactions. Mechanistically, mutation-induced structural changes in the YEATS domain, ENL's two disordered regions of opposing charges, and the incorporation of extrinsic elongation factors are all required for ENL condensate formation. Extensive mutagenesis establishes condensate formation as a driver of oncogenic gene activa-tion. Furthermore, expression of ENL mutants beyond the endogenous level leads to non-functional conden-sates. Our findings provide new mechanistic and functional insights into cancer-associated condensates and support condensate dysregulation as an oncogenic mechanism.

Automated summary

Growing evidence suggests the presence of transcriptional condensates on chromatin, but their formation mechanisms and functional significance are still unclear. This study reveals that mutations in the histone acetylation reader ENL can lead to aberrant condensate formation, which drives oncogenic gene activation in human cancer.