Tokushima University Elucidates 'Molecular Switch' Mechanism Controlling Transcription Factor Hub Formation via Phase Separation

On May 19, 2026, Tokushima University announced the elucidation of the activation mechanism for Heat Shock Factor 1 (Hsf1), a protein that functions when cells undergo stress.

### Key Highlights - Elucidated the mechanism by which Hsf1 clusters and activates through a reaction called biological phase separation upon binding with DNA. - Hsf1 is normally suppressed by internal interactions, but DNA binding triggers changes in atomic-level fluctuations, releasing this suppression and switching it to an active state. - This may lead to new drug discovery strategies targeting the regulation of protein fluctuations that trigger phase separation, particularly for transcription factors previously considered difficult to target.

### Research Details When cells are stressed, Hsf1 binds to target DNA and collectively activates group of genes that protect the cell. During this process, Hsf1 efficiently aggregates multiple transcription factors via phase separation, but the molecular mechanism converting local DNA recognition into phase separation was previously unknown. A research group led by Professor Tomohide Saio at Tokushima University utilized biophysical research methods, primarily solution Nuclear Magnetic Resonance (NMR) spectroscopy, to solve this mystery.

Specifically, in the steady state, the intrinsically disordered region (IDR) involved in driving phase separation is bound within the molecule to the DNA-binding domain (DBD), sequestering its activity. In contrast, upon DNA binding, the structural flexibility of the DBD increases, releasing the IDR and promoting phase separation through interactions between IDRs. This discovery provides a structural and thermodynamic basis for how information from DNA is converted into broad intracellular phase separation phenomena.

These results were published online in 'Angewandte Chemie International Edition' on May 19, 2026. Given that over-activation of Hsf1 enhances stress tolerance in cancer cells while reduced activity is linked to neurodegenerative diseases, this understanding of strict activity control is expected to contribute significantly to medicine.