Abstract IA022: Aberrant transcriptional condensates in cancer: Mechanisms and implications

Abstract

Abstract While growing evidence suggests the prevalence of nanoscale protein condensates on chromatin, their mechanisms of formation and functional significance in normal and disease states remain largely unclear. I will present our ongoing work linking aberrant condensates and cancer. In Wilms tumor and leukemia, a series of mutations in the histone acetylation reader ENL create gain-of-function mutants with increased transcriptional activation activity. We discover that these mutations, clustered in ENL’s structured acetyl-binding YEATS domain, trigger aberrant condensates at endogenous genomic targets through a network of multivalent homotypic and heterotypic interactions. Crystal structures of four different ENL mutant YEATS domains reveal structural changes critical for condensate formation. In addition, two oppositely charged disordered regions in ENL mutants play distinct yet complementary roles in regulating the initiation and growth of condensates. ENL mutant condensates enrich for an aberrantly high amount of transcription elongation factors which, in turn, also contribute to condensate formation. Importantly, perturbing these condensates in situ via extensive mutagenesis establish their causal role in oncogenic gene activation. Interestingly, expression of ENL mutants beyond endogenous levels results in larger droplet-like condensates that suppress oncogenic gene activation, indicating a dosage-sensitive function of oncogenic proteins prone to condensation. Together, by elucidating how cancer-associated transcriptional condensates occur and function, our work reveals a poorly recognized role of structured domains in the formation of biomolecular condensates and lends crucial experimental support to establish condensate dysregulation as an under-appreciated oncogenic mechanism. These insights would open new areas of investigation and nominate novel therapeutic approaches. Citation Format: Liling Wan. Aberrant transcriptional condensates in cancer: Mechanisms and implications. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA022.