The phenylalanine-and-glycine repeats of NUP98 oncofusions form condensates that selectively partition transcriptional coactivators
Description
Recurrent cancer-causing fusions of NUP98 produce higher-order assemblies known as condensates. How NUP98 oncofusion-driven condensates activate oncogenes remains poorly understood. Here, we investigate NUP98-PHF23, a leukemogenic chimera of the disordered FG-repeats-rich region of NUP98 and the H3K4me3/2- binding PHD finger domain of PHF23. Our integrated analyses using mutagenesis, proteomics, genomics, and condensate reconstitution demonstrate that the PHD domain targets condensates to H3K4me3/2-demarcated developmental genes while the FG repeats determine condensate composition and gene activation. The FG repeats are necessary to form condensates that partition a specific set of transcriptional regulators, notably the KMT2/MLL family of H3K4 methyltransferases, histone acetyltransferases and BRD4. The FG repeats are sufficient to partition these transcriptional regulators and activate a reporter when tethered to a locus. NUP98- PHF23 assembles the chromatin-bound condensates that partition multiple positive regulators, initiating a feed-forward loop of reading-and-writing active histone modifications. This network of interactions enforces an open chromatin landscape at proto-oncogenes, thereby driving cancerous transcriptional programs.