Congratulations to SFB1551 members Hao Ruan, Rodrigo Dillenburg, Elnaz Hosseini, Sina Wittmann, Martin Girard and Edward Lemke on their recent publication in Nature Communications: “Differential conformational expansion of NUP98-HOXA9 oncoprotein from nanosized assemblies to macrophases”.

This publication is the result of a joint collaboration within the SFB1551 framework, specifically tied to Project R12: “DNA-Facilitated Nano-assembly of Biological Block Co-polymers”. This project explores  how disordered protein regions fused to transcription factors form tiny, dynamic molecular clusters inside cells. By viewing these proteins as complex block copolymers, researchers combine theory and advanced imaging to uncover how their sequence design shapes clustering, DNA binding, and gene regulation.

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 a block copolymer architecture, with at least one block being a folded DNA interaction domain, and another block being highly enriched in intrinsic disorder. In this study, we focus on NUP98-HOXA9 (NHA9), a chimeric TF implicated in leukemogenesis. By integrating experiments and simulations, we examine the structural dynamics of NHA9’s FG domain across assembly states. We find 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. These findings offer molecular insight into the phase behaviour of NHA9 and highlight dynamic conformational transitions of intrinsically disordered regions during molecular assembly, with implications for understanding transcriptional regulation in cancer.