Transcription factors (TFs) play a central role in gene regulation by binding to specific DNA sequences and orchestrating the transcriptional machinery. A majority of eukaryotic TFs have block copolymer architecture, with at least one block being a folded DNA interaction domain and another block being highly enriched in intrinsic disorder. Multivalent interactions in the intrinsically disordered region (IDR) can contribute to phase separation into macroscopic condensates. In this study, we focus on NUP98-HOXA9 (NHA9), a chimeric transcription factor implicated in leukemogenesis, in which two FG-repeat-rich IDRs derived from NUP98 get fused to the C-terminal part of the transcription factor HOXA9. By integrating experiments and simulations, we examined the structural dynamics of NHA9's FG domain across assembly states. We found that the FG domain has different conformational compactness in the monomeric, oligomeric, and densely packed condensate state. Notably, the oligomeric state exhibits micelle-like organization with non-fixed stoichiometry, with the DNA-binding domain exposed at the periphery. While their architecture is non-random, their sizes depend on NHA9 concentration, consistent with non-core-shell spherical micelles. Molecular dynamics simulations support the expansion of NHA9’s FG domain as oligomeric assemblies grow in size and reveal micelle-like features in the resulting structure. These findings offer molecular insight into the phase behavior of NHA9 and highlight the dynamic conformational transitions of IDRs during condensate formation, with implications for understanding transcriptional regulation in cancer.
Girard et al. (Sun,) studied this question.