GATA3 Differentially Regulates the Transcriptome via Its Zinc Finger 2-Modulated Phase Separation

Phase separation (PS) underlies gene control by transcription factors. However, little is known about whether and how the DNA-binding domains (DBDs) regulate the PS for transcription factors to differentially regulate the transcriptome. The transcription factor GATA3, a master immune regulator, is frequently mutated in breast cancer. Here, we report that GATA3 undergoes its DBD-modulated PS to mediate the formation of chromatin condensates. We show that the DBD regulates the GATA3 PS through its zinc finger 2 (ZnF2), which provides positive charges for multivalent electrostatic interactions mainly via two arginine amino acids, R329 and R330. Breast cancer GATA3 with ZnF2-defective mutations, when compared to those without, cause aberrant ZnF2-modulated PS and condensates to remodel the differentially regulated transcriptome, resulting in a favorable prognosis for patients and reduced tumor growth in mice. Thus, GATA3 represents a principle of how a transcription factor differentially regulates the transcriptome via its DBD-modulated PS.